CN107001342B - Novel compounds - Google Patents

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CN107001342B
CN107001342B CN201580039289.0A CN201580039289A CN107001342B CN 107001342 B CN107001342 B CN 107001342B CN 201580039289 A CN201580039289 A CN 201580039289A CN 107001342 B CN107001342 B CN 107001342B
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methyl
chloro
phenyl
piperazin
carbonyl
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CN107001342A (en
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雷晖
马欣
任峰
林熹晨
小罗伯特.W.马奎斯
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GlaxoSmithKline Intellectual Property Development Ltd
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Abstract

The present invention relates to novel retinoid-related orphan receptor gamma (ROR γ) modulators and their use in the treatment of diseases mediated by ROR γ.

Description

Novel compounds
The present invention relates to novel retinoid-related orphan receptor gamma (ROR γ) modulators and their use in the treatment of diseases mediated by ROR γ.
Background
Retinoid-Related Orphan Receptors (RORs) are transcription factors belonging to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) adv. Dev. biol.16: 313) -355.) the ROR family consists of three members, ROR alpha (ROR α), ROR beta (ROR β) and ROR gamma (ROR γ), each of which is encoded by a separate gene (RORA, RORB and RORC, respectively). ROR comprises four main domains shared by most nuclear receptors, N-terminal A/B domain, DNA-binding domain, hinge domain and ligand-binding domain.
Although ROR γ 1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, ROR γ t is only expressed exclusively in cells of the immune system. ROR γ t has been identified as a key regulator of Th17 cell differentiation. Th17 cells are a subset of T helper cells that produce IL-17 and other proinflammatory cytokines. Th17 cells have been shown to have a key role in a variety of mouse autoimmune disease models, including Experimental Autoimmune Encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Furthermore, Th17 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept.Signal.7: e 003; Manel et al (2008) Nat. Immunol.9: 641-649; Miosec & Kolls (2012) Nat. Rev. drug.Discov.10: 763-776). The pathogenesis of chronic autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, results from the disruption of tolerance to self-antigens and the development of infiltration of target tissues by auto-invasive effector T cells. Studies have shown that Th17 cells are one of the important drivers of inflammatory processes in tissue-specific autoimmunity (Steinman (2008) J. exp. Med.205: 1517-. There is evidence that Th17 cells are activated during disease and are responsible for recruiting other inflammatory cell types, particularly neutrophils, to mediate pathology in target tissues (Korn et al (2009) annu. rev. immunol.27: 485-one 517).
ROR γ t plays a crucial role in the pathogenic response of Th17 cells (Ivanov et al (2006) Cell 126: 1121-1133). ROR γ t deficient mice showed very few Th17 cells. In addition, ROR γ t defects lead to improvements in EAE. Further evidence for the role of ROR γ t in the pathogenesis of autoimmune or inflammatory diseases can be found in the following references: jetten & Joo (2006) adv.Dev.biol.16: 313-355; meier et al (2007) Immunity 26: 643-654; aloisi & Pujol-Borrell (2006) nat. Rev. Immunol.6: 205-217; jager et al (2009) J.Immunol.183: 7169-7177; serafini et al (2004) Brain Pathol.14: 164-174; magliozzi et al (2007) Brain 130: 1089-1104; barnes (2008) nat. Rev. Immunol.8: 183-192; miosesec & Kolls (2012) nat. Rev. drug. Discov.10: 763-776.
In view of the role ROR γ plays in the pathogenesis of diseases, it would be desirable to prepare compounds capable of modulating ROR γ activity, which compounds are useful in the treatment of ROR γ mediated diseases.
Disclosure of Invention
The present invention relates to novel ROR γ modulators and their use in the treatment of diseases mediated by ROR γ. In particular, the present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof
Figure BDA0001212817760000021
Wherein R is1-R7As defined below.
In another aspect, the invention provides the use of a compound of formula I in the treatment of a disease mediated by ROR γ. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and ankylosing spondylitis. In yet another aspect, the invention relates to a method of treating said diseases.
Detailed Description
Terms and definitions
"alkyl" refers to a monovalent saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to alkyl groups having 1-6 member atoms. Alkyl groups may be optionally substituted with one or more substituents as defined herein. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.
"cycloalkyl" refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl is a monocyclic ring system or is a fused or bridged bicyclic ring system. For example, C3-C7 cycloalkyl refers to cycloalkyl groups having 3-7 member atoms. Cycloalkyl groups may be optionally substituted by one or more substituents as defined herein. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"enantiomeric excess" or "ee" is the excess of one enantiomer over the other, expressed as a percentage. Thus, when both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer is enriched so that it constitutes 95% of the product, then the enantiomeric excess will be 90% ee (amount of enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
"enantiomerically pure" refers to a product having an enantiomeric excess of 99% ee or greater.
"half-life" refers to the time required for half the amount of a substance to be converted into another chemically different species in vitro or in vivo.
"halo" refers to the halogen groups fluorine, chlorine, bromine, and iodine.
"heteroaryl" refers to an aromatic ring containing 1-4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted by one or more substituents as defined herein. Heteroaryl is a monocyclic ring system, or is a fused or bridged bicyclic ring system. Monocyclic heteroaryl rings have 5-7 member atoms. Bicyclic heteroaryl rings have 7-11 member atoms. Bicyclic heteroaryl rings include those wherein the phenyl is joined to the monocyclic heterocycloalkyl ring to form a fused, spiro, or bridged bicyclic ring system and those wherein the monocyclic heteroaryl ring is joined to the monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring to form a fused, spiro, or bridged bicyclic ring system. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furyl, furazanyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinoxalyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, furopyridyl and naphthyridinyl. As used herein, "5-6 membered monocyclic heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic group, said group or moiety comprising 5 or 6 ring atoms, including at least 1 carbon atom and 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered monocyclic heteroaryl groups contain 1 nitrogen, oxygen or sulfur ring heteroatom and optionally contain 1,2 or 3 additional nitrogen ring atoms. Selected 6-membered monocyclic heteroaryls contain 1,2 or 3 nitrogen ring heteroatoms. Illustrative examples of 5-6 membered monocyclic heteroaryls useful in the present invention include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and tetrazolyl.
"heteroatom" means a nitrogen, sulfur or oxygen atom.
"Heterocycloalkyl" means a saturated ring containing 1 to 4 heteroatoms as member atoms in the ring. However, the heterocycloalkyl ring is not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyl is a monocyclic ring system or is a fused, spiro or bridged bicyclic ring system. Monocyclic heterocycloalkyl rings have 4-7 member atoms. Bicyclic heterocycloalkyl rings have 7-11 member atoms. Examples of heterocycloalkyl include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, 1, 3-dioxolanyl, 1, 3-dioxanyl, 1, 3-oxathiolanyl, 1, 3-dithianyl, azetidinyl, oxetanyl, azabicyclo [3.2.1] octyl, and oxabicyclo [2.2.1] heptyl.
A "member atom" is one or more atoms that refers to a chain or ring. When more than one member atom is present in a chain or within a ring, each member atom is covalently bonded to an adjacent member atom in the chain or ring. The atoms that make up the substituents on the chain or ring are not member atoms of the chain or ring.
"optionally substituted" means that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, can be unsubstituted or substituted with one or more defined substituents.
"ROR γ" refers to all subtypes encoded by the RORC gene, which include ROR γ 1 and ROR γ t.
"ROR γ modulator" refers to a compound that directly or indirectly inhibits the activity of ROR γ. ROR γ modulators include antagonists and inverse agonists of ROR γ.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Reference to a group being "substituted" means that one or more hydrogen atoms attached to the member atoms in the group is replaced by a substituent selected from the group of defined substituents. It is to be understood that the term "substituted" includes the implicit designation that the substitution is in accordance with the allowed valency of the atom or substituents being substituted, and that the substitution results in a stable compound (i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, or elimination, and is sufficiently robust to withstand isolation from the reaction mixture). When it is stated that a group may contain one or more substituents, one or more (where appropriate) member atoms in the group may be substituted. Furthermore, individual member atoms in a group may be substituted with more than one substituent, provided that such substitution conforms to the allowed valences of the atoms.
Compound (I)
The present invention provides compounds of formula I or a pharmaceutically acceptable salt thereof.
Figure BDA0001212817760000051
Wherein:
R1comprises the following steps:
-a 5-6 membered monocyclic heteroaryl, optionally substituted with: i) c1-C5Alkyl optionally substituted by CF3Or CN, ii) CH2F; or iii)1-2 substituents independently selected from: halogen, methyl, methoxy and CN; wherein the 5-6 membered monocyclic heteroaryl is selected from: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and tetrazolyl, or an N-oxide thereof; or
-phenyl substituted with 1-2 substituents independently selected from: CN, halogen and methyl;
R2is C1-C3An alkyl group;
R3is halogen;
R4is H;
R5is C1-C3An alkyl group;
R6is H or methyl; and
R7is tetrahydrofuranyl or tetrahydropyranyl, wherein the tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with methyl.
In one embodiment, the present invention relates to compounds of formula I wherein:
R1is a-5-6 membered monocyclic heteroaryl, optionally substituted with: i) c1-C5Alkyl optionally substituted by CF3Or CN substitution, ii)CH2F; or iii)1-2 substituents independently selected from: halogen, methyl, methoxy and CN; or
-phenyl substituted with 1-2 substituents independently selected from: CN, halogen and methyl;
R2is C1-C3An alkyl group;
R3is halogen;
R4is H;
R5is C1-C3An alkyl group;
R6is H or methyl; and
R7is tetrahydrofuranyl or tetrahydropyranyl, wherein the tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with methyl.
In one embodiment, the invention relates to compounds of formula I wherein R1Comprises the following steps:
-thiazolyl or pyridyl, optionally substituted with: i) c1-C5Alkyl optionally substituted by CF3Or CN, ii) CH2F; or iii)1-2 substituents independently selected from: halogen, methyl, methoxy and CN; or
-phenyl substituted with 1-2 substituents independently selected from: CN, halogen and methyl.
In one embodiment, the invention relates to compounds of formula I wherein R1Is phenyl substituted with 1 or 2 substituents selected from CN and halogen. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is phenyl substituted by CN. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is phenyl substituted by CN and F.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is a 6 membered monocyclic heteroaryl substituted with 2 substituents independently selected from: methyl, halogen, CN and methoxy. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted with 2 substituents independently selected from the group consisting of: methyl, halogen, CN and methoxy. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted with 2 substituents independently selected from the group consisting of: methyl, F and CN. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted by methyl and F. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted by methyl and Cl. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted by methyl and CN. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is1Is pyridyl substituted by CN and F.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is2Is methyl.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is3Is Cl.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is5Is methyl. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is5Is ethyl.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is6Is H.
In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is7Is tetrahydrofuranyl, optionally substituted with methyl. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is7Is tetrahydrofuranyl. In one embodiment, the present invention also relates to compounds of any of the above embodiments, wherein R is7Is tetrahydropyranyl. In one embodiment, the present invention also relates to any of the aboveA compound of embodiment wherein R7Is methyl tetrahydrofuranyl.
In one embodiment, the invention relates to compounds of formula (I) wherein R1Is pyridyl substituted with: i) methyl and CN or ii) methyl and Cl, R2Is methyl, R3Is Cl, R4Is H, R5Is methyl, R6Is H and R7Is tetrahydrofuranyl.
In one embodiment, the invention relates to compounds of formula (I) wherein R1Is pyridyl substituted by methyl and F, R2Is methyl, R3Is Cl, R4Is H, R5Is methyl, R6Is H and R7Is tetrahydrofuranyl.
In another embodiment, the invention relates to compounds of formula (I), wherein R1Is phenyl substituted by CN, R2Is methyl, R3Is Cl, R4Is H, R5Is methyl, R6Is H and R7Is tetrahydrofuranyl or tetrahydropyranyl.
In another embodiment, the invention relates to compounds of formula (I), wherein R1Is phenyl substituted by CN and F, R2Is methyl, R3Is Cl, R4Is H, R5Is methyl, R6Is H and R7Is tetrahydrofuranyl.
In one embodiment, the compound of formula I is selected from:
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
3-cyano-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
3-cyano-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
(S) -3-cyano-N- (5-fluoro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
3-cyano-N- (5-fluoro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
3-cyano-N- (5-fluoro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
n- (5-chloro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluorobenzamide;
3-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-4-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-4-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3, 5-difluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3, 5-difluorobenzamide;
3-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-5-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-5-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
n- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
n- (5-chloro-3- (((S) -3-ethyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) -2-methylphenyl) -5-fluoro-6-methylnicotinamide;
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) nicotinamide;
5-fluoro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyanonicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6- (fluoromethyl) nicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6- (fluoromethyl) nicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methoxynicotinamide;
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-3- (((S) -3-ethyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) -2-methylphenyl) -6-methylnicotinamide;
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide; and
5- ((5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the compound of formula I is selected from:
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide; and
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the compound of formula I is selected from:
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide; and
5- ((5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I may contain one or more asymmetric centers (also known as chiral centers) and may therefore exist as individual enantiomers, diastereomers or other stereoisomers, or as mixtures thereof. Chiral centers such as chiral carbon atoms may also be present in substituents such as alkyl groups. When the stereochemistry of a chiral center present in formula I or any chemical structure illustrated herein is not specified, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds of formula I containing one or more chiral centers may exist as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.
Individual stereoisomers of compounds according to formula I containing one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, the splitting can be performed as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support (e.g., silica gel with a chiral ligand attached) or in the presence of a chiral solvent. One skilled in the art will appreciate that when the desired stereoisomer is converted to another chemical entity by one of the separation methods described above, additional steps are required to release the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or one enantiomer may be converted to the other by asymmetric transformation.
The compounds of formula I may also contain double bonds or other centers of geometric asymmetry. When the stereochemistry of the geometric asymmetric center present in formula I or any chemical structure illustrated herein is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in formula I, whether such tautomers exist in equilibrium or predominantly in one form.
In some embodiments, the compounds of formula I may be present as the free base or as the free acid.
In certain embodiments, the compounds of formula I may contain acidic functional groups. In certain other embodiments, the compounds of formula I may contain basic functional groups. Thus, one skilled in the art will appreciate that pharmaceutically acceptable salts of the compounds of formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds of formula I may be preferred over the respective free bases or free acids, as such salts may confer greater stability or solubility to the molecule, thereby facilitating formulation into dosage forms. Thus, the invention also relates to the use of pharmaceutically acceptable salts of the compounds of formula I.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form, respectively, with a suitable base or acid, respectively. Suitable pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse, j.pharm.sci. (1977)66, pages 1-19.
Salts of the disclosed compounds containing a basic amine or other basic functional group can be prepared by any suitable method known in the art, including treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (e.g., glucuronic acid or galacturonic acid), α -hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like), examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, pyrophosphate, succinate, suberate, caprate, propionate, fumarate, 1-bis-benzoate, fumarate, 1-hydroxybenzoate, tartrate, 2-xylenoate, tartrate, 1-hydroxybenzoate, and the like.
Salts of the disclosed compounds containing acidic functional groups can be prepared by reaction with a suitable base. Such pharmaceutically acceptable salts can be prepared with bases which provide pharmaceutically acceptable cations and include alkali metal salts (particularly sodium and potassium salts), alkaline earth metal salts (particularly calcium and magnesium salts), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N '-dibenzylethylenediamine, 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, tris- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, dehydroabietylamine, N' -bisdehydroabietylamine, glucosamine, N-methylglucamine, collidine, choline, quinine, quinoline, and basic amino acids (e.g., lysine and arginine).
Other salts which are not pharmaceutically acceptable may be used in the preparation of the compounds of the invention and these should be considered to form further aspects of the invention. These salts, for example trifluoroacetate, although not themselves pharmaceutically acceptable, may be used to prepare salts which are useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
If a compound of the invention containing a basic amine or other basic functional group is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base, where appropriate, having a higher pK than the free base form of the compounda. Similarly, if a compound of the invention containing an acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK than the free acid form of the compounda。
The term "compounds of the invention" as used herein refers to compounds of formula I (as the free base or free acid) and pharmaceutically acceptable salts thereof. The term "compounds of the invention" also appear in the present application and refer to compounds of formula I (as free bases or free acids) and pharmaceutically acceptable salts thereof.
The invention also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art will know how to synthesize the deuterated form of the compound of formula (I). Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, such as deuterated lithium aluminum hydride.
The compounds of the invention may be present in solid or liquid form. In the solid state, the compounds of the invention may be present in crystalline or amorphous form or mixtures thereof. For compounds of the invention in crystalline form, one skilled in the art will appreciate that pharmaceutically acceptable solvates may be formed, wherein solvent molecules are incorporated into the crystal lattice upon crystallization. Solvates may comprise non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or they may comprise water as the solvent (which is incorporated into the crystal lattice). Solvates in which water is the solvent (which is incorporated into the crystal lattice) are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions (compositions) containing variable amounts of water. The present invention includes all such solvates.
Those skilled in the art will also appreciate that certain compounds of the present invention that may exist in crystalline form (including various solvates thereof) may also exhibit polymorphism (i.e., the ability to occur with different crystal structures). These different crystalline forms are commonly referred to as "polymorphs". The present invention includes all such polymorphs. Polymorphs have the same chemical composition but different packing, geometric arrangements and other describable properties of the crystalline solid state. Thus, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically have different melting points, IR spectra and X-ray powder diffraction patterns, which can be used for identification. One skilled in the art will appreciate that different polymorphs can be prepared, for example, by changing or adjusting the conditions or reagents used in preparing the compounds. For example, changes in temperature, pressure or solvent can produce polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
The compounds of formula I and their pharmaceutically acceptable salts may be used alone or in combination with other therapeutic agents. The combination therapy of the present invention therefore comprises the administration of at least one compound of formula I or a pharmaceutically acceptable salt thereof and the use of at least one other therapeutically active agent. The compound of formula I or a pharmaceutically acceptable salt thereof and the other therapeutically active agent may be administered together or separately in a single pharmaceutical composition and, when administered separately, may be administered simultaneously or sequentially in any order.
In another aspect, there is provided a combination product comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents and optionally a pharmaceutically acceptable carrier or excipient.
Suitable other therapeutic agents include, but are not limited to, (1) TNF- α inhibitors, (2) non-selective COX-1/COX-2 inhibitors, (3) COX-2 inhibitors, (4) other agents for the treatment of inflammatory and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, buclizine, acrilamide, mizoribine, clobenzaprine, ciclesonide, hydroxychloroquine, d-penicillamine, chrysothiazole, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors, such as belimumab and CTLA-4-Ig or mimetics thereof, (5) leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (6) LTD4 receptor antagonists, (7) 4 inhibitors, (8) anti-TNF-4-gamma receptor agonists, (2) agonists, anti-1, interferon receptor agonists, interferon (I), anti-2) inhibitors, anti-interferon (interferon, or anti-receptor agonist (e), anti-7, anti-interferon (interferon), anti-interferon, anti-1, interferon, or anti-4, interferon (or anti-4) receptor (interferon), anti-4, interferon-4, or anti-4) anti-4, anti-interferon (interferon, anti-4, or anti-4, anti-interferon, anti-4, anti-interferon, anti-4, anti-4 or anti-interferon (e-interferon, anti-4-interferon, anti-parenteral or anti-interferon (e-4-or anti-interferon, anti-interferon (e-interferon, anti-or anti-interferon, anti-interferon (e-interferon, anti-4-interferon, anti-rat-interferon, anti-rat-4, anti-4-interferon, anti-rat-or anti-interferon, anti-rat-4, anti-or anti-rat-interferon, anti-rat-interferon, anti-rat-interferon (e, anti-rat-or anti-rat-interferon, anti-4-rat-4-rat-interferon, anti-rat-or anti-interferon, anti-4-interferon, anti-rat-.
Preparation of the Compounds
The compounds of formula I can be prepared using conventional organic synthesis. Suitable synthetic routes are described below in the general reaction schemes.
One skilled in the art will appreciate that if a substituent described herein is incompatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting various substituents using the suitable protecting groups are well known to those skilled in the art; examples of which can be found in t.greene and p.wuts,Protecting Groups in Chemical Synthesis(3 rd edition), John Wiley&Sons, NY (1999). In some cases, substituents that are reactive under the reaction conditions used may be specifically selected. In these cases, the reaction conditions convert the selected substituent to another substituent that is either useful in an intermediate compound or a desired substituent in the target compound.
Scheme 1
Figure BDA0001212817760000211
[ exemplary conditions: a) BH3·THF，THF，0℃-RT；b)PCC，CH2Cl2；c)NaBH(OAc)3，HOAc，DCM，3；d)Pd，H2Second, secondAlcohol, RT; e) r1CO2H，HOBt,EDC，DMF；f)TFA，DCM；g)R7CO2H，HOBt，EDC，DMF]。
Scheme 1 represents a general reaction scheme for the preparation of compounds of formula I, wherein R1-R7As defined above. The starting materials or reagents are commercially available or prepared from commercially available starting materials using methods known to those skilled in the art.
Benzoic acid 1 may be prepared from BH3THF reduction to afford benzyl alcohol 2. Alcohol 2 can be oxidized by PCC to the corresponding aldehyde and then reductively aminated with 3 to provide nitro compound 4. At H2By reduction of the nitro compound 4 with Pd in the presence of Pd to give an amine, which is reacted with various acids to give the amide 5. 5 was removed by treatment with TFA and the resulting amine was reacted with various acids to provide the final compound of formula I.
Scheme 2
Figure BDA0001212817760000212
[ exemplary conditions: a) TFA, DCM, RT; b) HATU, DIPEA, DMF; c) SnCl2.2H2O, ethanol, RT; d) r1CO2H，HATU，DIPEA，DMF]。
Scheme 2 represents another reaction scheme for the preparation of compounds of formula I, wherein R1-R7As defined above. The starting materials or reagents are commercially available or prepared from commercially available starting materials using methods known to those skilled in the art.
Boc protection on nitro compound 1 is removed by TFA to provide nitramine 2, which can then be reacted with various acids to give nitroamide 3. Reduction of the nitro group to an amine by tin (II) chloride dehydrate (dehydrate) gives the key intermediate 4, which is then condensed with various acids to give the final compound of formula I.
Examples
Abbreviations
ACN acetonitrile
DCE 1, 2-dichloroethane
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMAP N, N-dimethylpyridin-4-amine
DME 1, 2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DPPP 1, 3-bis (diphenylphosphino) propane
EA Ethyl acetate
EDC N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride
ESI electrospray ionization
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HOBt hydroxybenzotriazole
HPLC high performance liquid chromatography
LCMS liquid chromatography mass spectrometry
MDAP (minimization of drive-by-plate) mass spectrum-guided automatic preparative liquid chromatography
MS Mass Spectrometry
NMP N-methyl-2-pyrrolidone
PE Petroleum Ether
PCC pyridinium chlorochromate
PG protecting group
RT Room temperature
sat, saturation
SM starting Material
TEA Triethylamine
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
TMSCN trimethylsilyl cyanide
Chromatography
All chromatographies are carried out using silica gel columns unless otherwise mentioned.
LCMS conditions:
1) acid conditions:
mobile phase: water/acetonitrile with 0.05% TFA
Column: agilent SB-C184.6x30mm 1.8 m;
and (3) detection: MS and photodiode array Detector (PDA)
2) Alkaline conditions:
mobile phase: 10mM NH4HCO3Aqueous solution/acetonitrile
Column: waters Xbridge C184.6x50mm 3.5 m;
and (3) detection: MS and photodiode array Detector (PDA)
MDAP conditions:
1) acid conditions:
the instrument comprises the following steps: waters quality oriented automatic purification system
Column: waters Sunfire Prep C18 column (5um, 19X50mm)
Mobile phase: water/acetonitrile with 0.05% TFA
2) Alkaline conditions:
the instrument comprises the following steps: mass-guided automatic purification system
Column: xbridge Prep C18 column (5um, 19X50mm)
Mobile phase: water/acetonitrile containing 0.05% ammonia
In the following steps, intermediates are generally mentioned after each starting material. This is merely to aid the chemist in the art. The starting materials may not necessarily be prepared from the mentioned batches.
Description 1
5, 6-Dichloronicotinic acid methyl ester (D1)
Figure BDA0001212817760000241
A mixture of 5, 6-dichloronicotinic acid (5g) and thionyl chloride (3.10g) in methanol (20mL) was stirred overnight at 25 ℃. Cold water (100mL) was added and the resulting mixture was saturated NaHCO3Neutralizing the solution. The aqueous layer was extracted with DCM (2X 100mL) and the combined organic layers were extracted with Na2SO4And (5) drying. After filtration, the filtrate was concentrated in vacuo to give the title compound (5g) as a white solid. Ms (esi): c7H5Cl2NO2A theoretical value 205; measured value 206[ M + H]+。
Description 2
5, 6-Dimethylnicotinic acid methylester (D2)
Figure BDA0001212817760000242
Will K2CO3(1.342g), tricyclohexylphosphine (0.272g), Pd2(dba)3A mixture of (0.444g), methylboronic acid (0.291g) and methyl 5, 6-dichloronicotinate (D1, 1g) in 1, 4-dioxane (20mL) was heated to 110 ℃ overnight. Cold water (30mL) was added and the aqueous layer was extracted with DCM (2X 100 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with EA: PE ═ 0% to 50%) to give the title compound (1g) as a yellow oil. Ms (esi): c9H11NO2A theoretical value of 165; found 166[ M + H]+。
Description 3
5, 6-Dimethylnicotinic acid (D3)
Figure BDA0001212817760000243
A mixture of sodium hydroxide (121mg) and methyl 5, 6-dimethylnicotinate (D2, 500mg) in methanol (10mL) and water (10mL) was stirred for 2 hours. Cold water (50mL) was added and the pH of the resulting mixture was adjusted to 5 with HCl solution (7M). The aqueous layer was extracted with DCM (2X 100 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated in vacuo to give the title compound (400mg) as a white solid. Ms (esi): c8H9NO2A theoretical value of 151; found value of 152[ M + H]+。
Description 4
5-chloro-6-methylnicotinate (D4)
Methyl 5, 6-dichloronicotinate (D1, 2g), methylboronic acid (0.581g), K2CO3(2.68g) and Pd (PPh)3)4(0.561g) mixture in 1, 4-dioxane (100mL) was stirred at 75 deg.C overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was further purified by column chromatography (eluting with EA: PE ═ 50% to 100%) to give the title compound (420mg) as a yellow solid. Ms (esi): c8H8ClNO2A theoretical value of 185; found value of 186[ M + H]+。
Description 5
5-chloro-6-methylnicotinic acid (D5)
Figure BDA0001212817760000252
A mixture of methyl 5-chloro-6-methylnicotinate (D4, 450mg), sodium hydroxide (485mg) in methanol (20mL) and water (5mL) was stirred at room temperature for 1 hour. HCl solution (4M) was used to adjust the pH to 4. The solution was concentrated and extracted with EA (20 mL). The organic phase was washed with water (2X 10mL) and Na2SO4Dried and concentrated in vacuo to give the title compound (400mg) as a white solid. Ms (esi): c7H6ClNO2A theoretical value 171; found value of 172[ M + H]+。
Description 6
5-bromo-3-methyl-2-cyanopyridine (D6)
Figure BDA0001212817760000253
To a solution of 2, 5-dibromo-3-methylpyridine (5g) in DMF (20mL) was added cuprous cyanide (1.785 g). The mixture was stirred at 120 ℃ overnight and then cooled to room temperature. The mixture was partitioned between EA (50mL) and water (50 mL). The organic layer was washed with brine (50mL) and Na2SO4Dried and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with EA: PE ═ 20%) to give the title compound (600mg) as a white solid. Ms (esi): c7H5BrN2A theoretical value of 195; found value of 196[ M + H]+。
Description 7
6-cyano-5-methylnicotinic acid methyl ester (D7)
Figure BDA0001212817760000261
Reacting 5-bromo-3-methyl-2-cyanopyridine (D6, 700mg), Pd (OAc)2A mixture of (160mg), DPPP (394mg) and TEA (1.486mL) in methanol (12mL) and DMF (3mL) was heated to 120 ℃ under an atmosphere of CO (10atm) for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography (eluting with EA: PE ═ 20%) to give the title compound (300mg) as a viscous oil. Ms (esi): c9H8N2O2A theoretical value of 176; found 177[ M + H [ ]]+。
Description 8
6-cyano-5-methylnicotinic acid (D8)
Figure BDA0001212817760000262
A mixture of methyl 6-cyano-5-methylnicotinate (D7, 250mg) and LiOH (68.0mg) in THF (15mL) and water (5mL) was stirred at room temperature overnight. The mixture was partitioned between water (10mL) and EA (16 mL). The aqueous phase was acidified with HCl solution (1M) to adjust the pH to about 6 and then extracted with EA (20 mL). The organic phase was washed with Na2SO4Dried, filtered and concentrated in vacuo to give the title compound (160mg) as a pale solid. Ms (esi): c8H6N2O2A theoretical value 162; found value of 163[ M + H]+。
Description 9
3-carboxy-5-fluoropyridine 1-oxide (D9)
Figure BDA0001212817760000271
To 5-fluoronicotinic acid (2g) in (CH)3CO)2O(5mL) and acetic acid (5mL) was added aqueous hydrogen peroxide (30%, 4.82 g). The mixture was stirred at 110 ℃ for 2 hours and then cooled to room temperature. Water (50mL) was added. The mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with saturated NaHCO3The solution (50mL), water (50mL) and brine (50mL) were washed. The solution was washed with MgSO4Drying and evaporation in vacuo gave the title compound (2g) as a white solid. Ms (esi): c6H4FNO3A theoretical value of 157; found value of 158[ M + H]+。
Description of the preferred embodiments 10
5-cyano-2-hydroxy-6-methylnicotinic acid ethyl ester (D10)
Figure BDA0001212817760000272
In a round-bottom flask, a mixture of diethyl 2- (ethoxymethylene) malonate (21.6g) and (E) -3-aminobut-2-enenitrile (8.20g) was stirred at 150 ℃ for 2 hours and left to stand overnight. The mixture was filtered. The precipitate was washed with ice-cold methanol to give the title compound (5g) as a yellow solid. Ms (esi): c10H10N2O3A theoretical value 206; found value 207[ M + H]+。
Description of the preferred embodiments 11
2-chloro-5-cyano-6-methylnicotinic acid ethyl ester (D11)
Figure BDA0001212817760000273
In a round-bottom flask, a mixture of ethyl 5-cyano-2-hydroxy-6-methylnicotinate (D10, 3mg) and phosphorus oxychloride (22.3mg) was stirred at 90 ℃ for 5 hours and allowed to stand overnight. The solution was concentrated in vacuo. The residue was poured onto ice. The resulting mixture was filtered to give the title compound (3g) as a yellow solid. Ms (esi): c10H9ClN2O2A theoretical value 224; found value of 225[ M + H]+。
Description of the preferred embodiments 12
5-cyano-6-methylnicotinic acid ethyl ester (D12)
Figure BDA0001212817760000281
To a mixture of ethyl 2-chloro-5-cyano-6-methylnicotinate (D11, 1.5g), methanol (50mL) and palladium (10% on carbon, 0.071g) was added ammonium formate (6.32 g). The mixture was stirred at room temperature for 3 hours, and then filtered. The solution was concentrated in vacuo. The residue was purified by column chromatography (eluting with PE: EA ═ 20%) to give the title compound (1g) as a white solid. Ms (esi): c10H10N2O2A theoretical value of 190; measured value 191[ M + H]+。
Description 13
5-cyano-6-methylnicotinic acid (D13)
Figure BDA0001212817760000282
To a mixture of ethyl 5-cyano-6-methylnicotinate (D12, 1g), methanol (15mL) and water (30mL) was added sodium hydroxide (2.103 g). The mixture was stirred at room temperature for 30 min. The pH of the solution was adjusted to 4 with hydrochloric acid. The mixture was washed with EA (2X 100 mL). The combined organic layers were concentrated in vacuo to give the title compound (800mg) as a white solid.1H NMR(400MHz，MeOD-d4)：9.20(s，1H)，8.62(s，1H)，2.83(s，3H)。MS(ESI)：C8H6N2O2A theoretical value 162; found value of 163[ M + H]+。
Description 14
2, 6-dichloro-5-fluoronicotinic acid methyl ester (D14)
To a mixture of 2, 6-dichloro-5-fluoronicotinic acid (5g) and one drop of DMF in DCM (20mL) was added oxalyl chloride (5mL) dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, then concentrated. The resulting acid chloride was redissolved in DCM (10mL) and added dropwise to DCM (20mL) and MeOH (20mL)In the mixture. The resulting mixture was stirred at room temperature for another 1 hour, then concentrated to give the title compound (6g) as an oil. Ms (esi): c7H4Cl2FNO2A theoretical value 223; found 224[ M + H]+。
Description of the preferred embodiments 15
2-chloro-5-fluoro-6-methylnicotinate (D15)
Figure BDA0001212817760000291
Methyl 2, 6-dichloro-5-fluoronicotinate (D14, 6g), 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriborole (trioxatriborine) (3.36g), K2CO3(9.99g) and Pd (Ph)3P)4(1.548g) the mixture in 1, 4-dioxane (50mL) was heated to 110 ℃ for 20 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (eluting with EA: PE ═ 1: 10) to give the title compound (3.5g) as an oil. Ms (esi): c8H7ClFNO2A theoretical value 203; measured value 204[ M + H]+。
Description 16
5-fluoro-6-methylnicotinate (D16)
Figure BDA0001212817760000292
A mixture of methyl 2-chloro-5-fluoro-6-methylnicotinate (D15, 4.2g), Pd/C (0.5g), and sodium acetate (6.77g) in EA (50mL) was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (eluting with EA: PE ═ 1: 10) to give the title compound (3.5g) as a white solid. Ms (esi): c8H8FNO2Theoretical value 169; measured value of 170[ M + H]+。
Description of the preferred embodiments 17
5-fluoro-6-methylnicotinic acid (D17)
Figure BDA0001212817760000301
To a solution of methyl 5-fluoro-6-methylnicotinate (D16, 2.3g) in THF (10mL) and methanol (10mL) was added a solution of NaOH (0.707g) in water (5 mL). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. To the residue was added water (5 mL). The pH of the mixture was adjusted to 3. The solid was collected and dried in vacuo to give the title compound (800mg) as a white solid.1HNMR(400MHz，DMSO-d6)：8.83(s，1H)，8.00(dd，J＝1.2Hz，9.6Hz，1H)，2.57(s，3H)。MS(ESI)：C7H6FNO2A theoretical value of 155; measured value 156[ M + H]+。
Description 18
3-cyano-4-methylbenzoic acid (D18)
A mixture of 3-iodo-4-methylbenzoic acid (3.0g) and copper (I) cyanide (1.333g) in DMF (12mL) was stirred at 100 ℃ for 20 h. The mixture was poured into ice water and extracted with EA. The organic phase was concentrated. The residue was washed with a mixed solvent of PE: EA (5:1) to give the title compound (800mg) as a green solid. Ms (esi): c9H7NO2A theoretical value 161; found 160[ M-H [)]-。
Description 19
5-fluoro-2-methyl-3-nitrobenzoic acid (D19)
Figure BDA0001212817760000303
5-fluoro-2-methylbenzoic acid (20g) was added portionwise to ice-cold concentrated sulfuric acid (98%, 80 mL). The mixture was stirred at 0 ℃ until all solids dissolved. Nitric acid (65%, 6mL) and H2SO4(98%, 12mL) was added in portions and then gradually warmed to room temperature. The resulting mixture was stirred at room temperature for 6 hours, then poured onto ice (500 mL). The solid was collected and washed with water (100 mL). Redissolving the solidIn EA (200mL) and washed with brine. The organic layer was washed with anhydrous Na2SO4Dried and concentrated in vacuo to give the title compound (11g) as a brown solid. Ms (esi): c8H6FNO4A theoretical value of 199; found value 198[ M-H]-。
Description 20
5-chloro-2-methyl-3-nitrobenzoic acid (D20)
To 5-chloro-2-methylbenzoic acid (50g) in concentrated H at 0 deg.C2SO4To the solution in (300mL) was added in portions a mixture of nitric acid (65%, 1.92g) and concentrated sulfuric acid (50 mL). The mixture was stirred for 6 hours and then poured onto ice (1 kg). The resulting mixture was diluted with water (100 mL). After filtration, the solid was collected and redissolved in EA (300 mL). The solution was washed with brine and Na2SO4Dried, filtered and concentrated in vacuo. The residue was washed twice with EA and PE (2:1, 50mL) to give the title compound (39g) as a yellow solid. Ms (esi): c8H6ClNO4A theoretical value of 215; found value of 216[ M + H]+。
Description of the preferred embodiments 21
(5-fluoro-2-methyl-3-nitrophenyl) methanol (D21)
Figure BDA0001212817760000312
5-fluoro-2-methyl-3-nitrobenzoic acid (D19, 11g) and BH3A mixture of THF (1M in THF, 72mL) was heated to 80 ℃ for 2 hours. MeOH (20mL) was added slowly to the mixture to quench the reaction. The resulting solution was concentrated in vacuo. The residue was dissolved in DCM (50mL) and saturated NaHCO3The solution (2X 50mL) and brine (2X 50mL) were washed. The organic phase was washed with Na2SO4Dried, filtered and concentrated to give the title compound (9g) as a yellow solid. Ms (esi): c8H8FNO3A theoretical value of 185; is not obtainedMeasured value of quality.
Description of the preferred embodiments 22
(5-chloro-2-methyl-3-nitrophenyl) methanol (D22)
Figure BDA0001212817760000321
To a mixture of 5-chloro-2-methyl-3-nitrobenzoic acid (D20, 10.7g) in THF (60mL) at 0 deg.C was added BH in portions3THF (1M in THF, 99 mL). The mixture was gradually warmed to room temperature and stirred for 5 hours. MeOH (50mL) was added slowly to the mixture. The mixture was concentrated in vacuo to give the title compound (8.5 g).1H NMR(400MHz，CDCl3)：7.67(s，1H)，7.65(s，1H)，4.73(d，2H)，2.33(s，3H)。
Description 23
5-chloro-1- (chloromethyl) -2-methyl-3-nitrobenzene (D23)
Figure BDA0001212817760000322
(5-chloro-2-methyl-3-nitrophenyl) methanol (D22, 7g) was dissolved in thionyl chloride (24.78 g). After stirring at 80 ℃ overnight, the mixture was concentrated to give the title compound (7g) as a yellow solid. Ms (esi): c8H7Cl2NO2A theoretical value 219; no measured value of quality was obtained.
Description 24
5-fluoro-2-methyl-3-nitrobenzaldehyde (D24)
Figure BDA0001212817760000323
To a mixture of (5-fluoro-2-methyl-3-nitrophenyl) methanol (D21, 9g) in DCM (100mL) was added PCC (14g) in portions. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give a crude product which was purified by column chromatography (eluting with EA: PE ═ 5%) to give the title compound (5g) as a pale yellow solid. Ms (esi): c8H6FNO3Theory of the inventionA value of 185; no measured value of quality was obtained.
Description 25
(S) -4- (5-chloro-2-methyl-3-nitrobenzoyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D25)
Figure BDA0001212817760000331
To a solution of 5-chloro-2-methyl-3-nitrobenzoic acid (D20, 32.3g), (S) -tert-butyl 2-methylpiperazine-1-carboxylate (25g) and DIPEA (43.6mL) in DMF (100mL) was added HATU (57.0g) at 0 ℃. The mixture was stirred at room temperature overnight and then poured into water. The resulting mixture was filtered. The solid was dissolved in EA and washed three times with brine. The solution was taken with Na2SO4Dried and concentrated in vacuo to give the title compound (47g) as a bright orange solid. Ms (esi): c18H24ClN3O5A theoretical value 397; found 342[ M-tBu + H]+。
Description 26
(S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D26)
Figure BDA0001212817760000332
To a solution of 5-fluoro-2-methyl-3-nitrobenzaldehyde (D24, 10g) and tert-butyl (S) -2-methylpiperazine-1-carboxylate (12.03g) in DCM (120mL) was added a few drops of acetic acid (3.28 g). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (23.15g) was added to the ice bath. The mixture was stirred at room temperature overnight and saturated NaHCO was used3The solution was quenched. The organic layer was washed with anhydrous Na2SO4Drying, filtration and concentration in vacuo gave the title compound (22.17g) as a syrup. Ms (esi): c18H26FN3O4A theoretical value 367; measured value 368[ M + H]+。
Description 27
(S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D27)
Figure BDA0001212817760000341
At 0 ℃ adding BH3THF (1.0M solution in THF, 151mL) was added dropwise to a solution of tert-butyl (S) -4- (5-chloro-2-methyl-3-nitrobenzoyl) -2-methylpiperazine-1-carboxylate (D25, 30g) in THF (200mL) over 10 min. The reaction mixture was heated to 75 ℃ and stirred for 1 hour. The resulting mixture was concentrated to give the title compound (28g) as a yellow oil. Ms (esi): c18H26ClN3O4Theoretical value 383; found value of 384[ M + H]+。
Description of the preferred embodiments 28
(S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-ethylpiperazine-1-carboxylic acid tert-butyl ester (D28)
Figure BDA0001212817760000342
To a solution of 5-chloro-1- (chloromethyl) -2-methyl-3-nitrobenzene (D23, 1.232g) in DMF (20mL) at 60 ℃ was added (S) -2-ethylpiperazine-1-carboxylic acid tert-butyl ester (1g) and K2CO3(1.935 g). After stirring overnight, the mixture was poured into ice/water and then extracted with DCM (3 × 100 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated to give a yellow oil which is purified by column chromatography (eluting with EA: PE ═ 5%) to give the title compound (1.3g) as a yellow solid. Ms (esi): c19H28ClN3O4A theoretical value 397; found value 398[ M + H]+。
Description 29
(S) -4- (3-amino-5-fluoro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D29)
Figure BDA0001212817760000343
To (S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D26, 5g) under hydrogenTo a solution in ethanol (65mL) was added palladium (0.145 g). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated in vacuo to give the title compound (4.5 g). Ms (esi): c18H28FN3O2A theoretical value 337; found value 338[ M + H]+。
Description of the preferred embodiments 30
(S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D30)
Figure BDA0001212817760000351
To a stirred solution of (S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D27, 30g) and nickel (4.59g) in methanol (200mL) at 50 ℃ under nitrogen atmosphere was added hydrazine (80%, 12.26 mL). The reaction mixture was stirred at 50 ℃ for 1 hour. The catalyst was filtered and the filtrate was concentrated. The residue was dried in vacuo to give the title compound (27g) as a bright yellow oil. Ms (esi): c18H28ClN3O2A theoretical value 353; found 354[ M + H [)]+。
Description 31
(S) -1- (5-fluoro-2-methyl-3-nitrobenzyl) -3-methylpiperazine, dihydrochloride (D31)
Figure BDA0001212817760000352
To a solution of (S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D26, 4g) in DCM (15mL) was added HCl/MeOH (27.2 mL). The mixture was degassed and stirred at room temperature under nitrogen for 12 hours. The mixture was concentrated to give the title compound (3.1 g). Ms (esi): c13H18FN3O2Theoretical value 267; found value 268[ M + H]+。
Description 32
(S) -1- (5-chloro-2-methyl-3-nitrobenzyl) -3-methylpiperazine (D32)
To a solution of (S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D27, 1.5138g) in DCM (15mL) was added TFA (3.04mL) dropwise. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was diluted with DCM (10mL) and saturated Na2CO3The solution was basified to pH 9. NaOH solution (2M) was added to adjust the pH to 11. The aqueous phase was separated and extracted with DCM (2X 15 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated to give the title compound (1.17g) as a pale yellow oil. Ms (esi): c13H18ClN3O2Theoretical value 283; found value of 284[ M + H]+。
Description 33
(S) -1- (5-chloro-2-methyl-3-nitrobenzyl) -3-ethylpiperazine, dihydrochloride (D33)
Figure BDA0001212817760000361
To a solution of (S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-ethylpiperazine-1-carboxylic acid tert-butyl ester (D28, 1.3g) in methanol (30mL) was added a solution of HCl (1.191g) in MeOH. The mixture was stirred at room temperature for 18 h, then concentrated in vacuo to give the title compound (900mg) as a white solid. Ms (esi): c14H20ClN3O2Theoretical value 297; found value of 298[ M + H [)]+。
Description 34
(S) -4- (5-chloro-3- (3-cyanobenzoylamino) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D34)
Figure BDA0001212817760000362
To a suspension of 3-cyanobenzoic acid (3.06g) in DCM (30mL) was added two drops of DMF. Oxalyl chloride (1.948mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. Mixing the solvent with waterAnd vacuum-removed. The residue was redissolved in acetonitrile (10 mL). The solution was added dropwise to a mixture of (S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D30, 6.7g) and potassium carbonate (7.85g) in acetonitrile (50 mL). The mixture was stirred overnight and then quenched with water (10 mL). The resulting mixture was filtered and the solid was washed with DCM (20 mL). The filtrate was concentrated to dryness and then dissolved in DCM (50 mL). The DCM solution was taken up with saturated Na2CO3Washing with Na2SO4Drying and filtering. The residue was purified by column chromatography (eluting with DCM: MeOH ═ 1:0-99: 1) to give the title compound (5.99g) as an off-white foamy solid. Ms (esi): c26H31ClN4O3A theoretical value 482; found 483[ M + H]+。
Description of 35 to 36
Descriptions 35-36 were prepared using procedures analogous to those described for description 34.
D35 tert-butyl (S) -4- (5-chloro-3- (6-ethylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate
D36 tert-butyl (S) -4- (5-chloro-2-methyl-3- (6-methylnicotinamido) benzyl) -2-methylpiperazine-1-carboxylate
Figure BDA0001212817760000371
Description 37
(S) -4- (5-chloro-3- (3-cyano-4-fluorobenzamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester, trifluoroacetate salt (D37)
Figure BDA0001212817760000372
To a solution of (S) -tert-butyl 4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D30, 220.5mg) and 3-cyano-4-fluorobenzoic acid (114.5mg) in DCM (10mL) was added DMAP (7.4mg) and EDC (250.8 mg). The mixture was stirred overnight. The mixture was diluted with DCM (10mL) and washed with water (5 mL). The organic layer was separated and concentrated to dryness. Removing the residueThe residue was purified by reverse phase chromatography (eluting with ACN/water (containing 0.05% TFA), with ACN% 10% -95%, 50mL/min) to give the title compound (315.3mg) as a light yellow solid. Ms (esi): c26H30ClFN4O3A theoretical value of 500; measured value 501[ M + H]+。
Description of 38 to 39
Descriptions 38-39 were prepared using procedures analogous to those described for description 37.
D38 tert-butyl (S) -4- (5-chloro-3- (3-cyano-4-methylbenzamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate, trifluoroacetate salt
D39 tert-butyl (S) -4- (3- (3-cyanobenzoylamino) -5-fluoro-2-methylbenzyl) -2-methylpiperazine-1-carboxylate, trifluoroacetate salt
Description 40
(S) -4- (5-chloro-3- (5-fluoro-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D40)
Figure BDA0001212817760000382
A solution of (S) -tert-butyl 4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D30, 913mg), 5-fluoro-6-methylnicotinic acid (D17, 400mg), HATU (980mg), and DIPEA (0.450mL) in DCM (100mL) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to give the title compound (1.2g) as a red oil. Ms (esi): c25H32ClFN4O3A theoretical value of 490; measured value 491[ M + H]+。
Description 41
Description 41 was prepared using procedures analogous to those described in description 40, with the specific reaction bases or solvents listed in the table below.
D41 tert-butyl (S) -4- (5-chloro-3- (2-cyanoisonicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate, trifluoroacetate salt
Figure BDA0001212817760000391
Description 42
(S) -4- (5-chloro-3- (5-cyano-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester, trifluoroacetate salt (D42)
Figure BDA0001212817760000392
To a solution of (S) -tert-butyl 4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D30, 264.5mg) and 5-cyano-6-methylnicotinic acid (D13, 158mg) in anhydrous DMF (5mL) was added HATU (510.3mg) and DIPEA (0.261mL), and the reaction mixture was stirred over the weekend. Dilute with DCM (10mL), wash twice with water (5mL × 2), concentrate the organic layer to dryness, purify the crude product by reverse phase chromatography (Biotage, SNAP Cartridge, KP-C18-HS 120g column, ACN/water (containing 0.05% TFA), ACN% ═ 10% -90%, 50mL/min) to give the title compound (350.8mg) as an off-white solid.1H NMR(400MHz，CDCl3)δppm 1.33(d，3H)，1.44(s，9H)，2.27(s，3H)，2.51-2.67(m，1H)，2.77-2.84(m，1H)，2.88(s，3H)，3.14(d，1H)，3.28(br s，1H)，3.41(d，1H)，3.94-4.17(m，3H)，4.46(brs，1H)，7.24(s，1H)，7.63(s，1H)，8.53(s，1H)，8.89(br s，1H)，9.25(s，1H)。19F NMR(376MHz，CDCl3)δppm-75.5。MS(ESI)：C26H32ClN5O3Theoretical value 497; found 498[ M + H]+。
Description 43-45
Descriptions 43-45 were prepared using procedures analogous to those described in description 40, with the specific reaction bases or solvents listed in the table below.
D43 tert-butyl (S) -4- (5-chloro-3- (6-cyanonicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate, trifluoroacetate salt
D44 (S) -3- ((3- ((4- (tert-butyloxycarbonyl) -3-methylpiperazin-1-yl) methyl) -5-chloro-2-methylphenyl) carbamoyl) -5-fluoropyridine 1-oxide
D45 tert-butyl (S) -4- (5-chloro-3- (5-fluoronicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate
Figure BDA0001212817760000401
Description 46
(S) -4- (5-chloro-3- (3-cyano-5-fluorobenzamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D46)
To a solution of 3-cyano-5-fluorobenzoic acid (200mg) in DCM (20mL) was added thionyl chloride (288 mg). The mixture was stirred at 40 ℃ for 8 hours and then concentrated to dryness under reduced pressure. The residue was redissolved in DCM (20 mL). The resulting solution was slowly added to a mixture of (S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D30, 429mg) and DIPEA (470mg) in DCM (20mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 1 hour. The resulting mixture was then partitioned with water (15 mL). The organic phase was washed with Na2SO4Dried, filtered and concentrated in vacuo to give the title compound (320mg) as a yellow solid. Ms (esi): c26H30ClFN4O3A theoretical value of 500; measured value 501[ M + H]+。
Description 47-48
Descriptions 47-48 were prepared using procedures analogous to those described in description 46.
D47 tert-butyl (S) -4- (5-chloro-2-methyl-3- (2-methylthiazole-5-carboxamido) benzyl) -2-methylpiperazine-1-carboxylate
D48 tert-butyl (S) -4- (5-chloro-3- (6-cyano-5-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate
Figure BDA0001212817760000411
Description 49
(S) -4- (5-chloro-3- (6-cyano-5-fluoronicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D49)
Figure BDA0001212817760000412
To a solution of (S) -3- ((3- ((4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl) methyl) -5-chloro-2-methylphenyl) carbamoyl) -5-fluoropyridine 1-oxide (D44, 500mg) in CH3To a solution in CN (20mL) was added TMSCN (0.204mL) and TEA (0.212 mL). The mixture was stirred at 80 ℃ for 2 hours. After cooling to room temperature, water was added. The mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with saturated NaHCO3The solution, water and brine were washed. The resulting solution was diluted with MgSO4Drying and filtering. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluting with EA: PE ═ 20%) to give the title compound (250mg) as a white solid. Ms (esi): c25H29ClFN5O3A theoretical value 501; found 502[ M + H]+。
Description 50
(S) -3-cyano-N- (5-fluoro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) benzamide (D50)
Figure BDA0001212817760000421
To a solution of (S) -4- (3- (3-cyanobenzoylamino) -5-fluoro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester, trifluoroacetate (D39, 4.2g) in DCM (60mL) was added TFA (20.81mL) with stirring at room temperature. The resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature and saturated Na was added2CO3The solution was carefully quenched. The pH was adjusted to about 10. The aqueous phase was separated and extracted five times with THF/EA. The combined organic phases were concentrated in vacuo to a volume of about 100 mL. Then the solution is mixed with Na2SO4Dried, filtered and concentrated to give the title compound (2.8 g). Ms (esi): c21H23FN4Theoretical value of O366; value of examination 367[M+H]+。
Description 51
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-methylnicotinamide, dihydrochloride (D51)
Figure BDA0001212817760000422
A mixture of (S) -4- (5-chloro-2-methyl-3- (6-methylnicotinamido) benzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D36, 1.0g) in DCM (6mL) was added to a HCl solution (4M in dioxane, 1.057 mL). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to give the title compound (1.07g) as a bright yellow solid. Ms (esi): c20H25ClN4A theoretical value of O372; found value 373[ M + H]+。
Description 52
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52)
Figure BDA0001212817760000431
To a solution of (S) -4- (5-chloro-3- (3-cyanobenzoylamino) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D34, 5.99g) in DCM (20mL) was added TFA (9.55mL) dropwise at room temperature. The mixture was heated at 40 ℃ for 2 hours. The solvent was removed in vacuo. The residue was taken up with saturated Na2CO3The solution was neutralized to pH 10 and then extracted with DCM (2 × 50 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated to give the title compound (4.89g) as a pale yellow solid. Ms (esi): c21H23ClN4Theoretical value of O: 382; found 383[ M + H]+。
Descriptions 53 to 54
Descriptions 53 and 54 were prepared using procedures similar to those described in description 52.
D53 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide
D54 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide
Figure BDA0001212817760000432
Description 55
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (D55)
To a solution of (S) -4- (5-chloro-3- (5-fluoro-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D40, 900mg) in DCM (10mL) was added TFA (1.130mL) dropwise and the reaction mixture was stirred at room temperature over the weekend. LCMS showed reaction completion. With saturated Na2CO3The solution was neutralized to pH 10, extracted and the aqueous layer was extracted twice with DCM (10mL × 2). The combined organic layers were washed with Na2SO4And (5) drying. Filtration and concentration of the filtrate to dryness gave the title compound (686.9mg) as a yellow solid (95% purity).1H NMR(400MHz，CDCl3)δppm 1.01(d，3H)，1.71(t，1H)，2.04(td，1H)，2.27(s，3H)，2.62(d，3H)，2.70(d，2H)，2.76-2.84(m，1H)，2.87(d，1H)，2.95(d，1H)，3.33-3.50(m，2H)，7.18(s，1H)，7.72(brs，1H)，7.81(brs，1H)，7.87(d，1H)，8.77(s，1H)。19F NMR(376MHz，CDCl3)δppm-122.7。MS(ESI)：C20H24ClFN4Theoretical value of O390; found value 391[ M + H]+。
Description 56
Description 56 was prepared using a procedure similar to that described in description 52.
D56 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide
Figure BDA0001212817760000441
Description 57
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (D57)
Figure BDA0001212817760000442
To a solution of (S) -4- (5-chloro-3- (5-cyano-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D42, 3.08g) in DCM (12mL) was added TFA (4.29mL) dropwise at room temperature. The reaction mixture was stirred overnight and LCMS showed the reaction was complete. Dilute with DCM (20mL) and saturate Na2CO3The aqueous solution was neutralized to pH 10 and then 2M aqueous NaOH was added until pH 11. Extract and re-extract the aqueous layer with DCM (10 mL). The combined organic layers were washed with Na2SO4And (5) drying. Filtration and concentration of the filtrate to dryness gave the title compound (2.6g) as a yellow solid (92% purity on LCMS). Ms (esi): c21H24ClN5A theoretical value of O397; found value 398[ M + H]+。
Description 58
Description 58 was prepared using similar procedures as described in description 52.
D58 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-cyanonicotinamide
Figure BDA0001212817760000451
Description 59
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide (D59)
Figure BDA0001212817760000452
A solution of (S) -4- (5-chloro-3- (6-ethylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D35, 1.6g) and aqueous HCl (4M, 3.29mL) in DCM (10mL) was stirred 1And (4) hours. Cold water (30mL) was added. The resulting mixture was taken up in saturated NaHCO3Neutralizing the solution. The aqueous layer was extracted with DCM (2X 100 mL). The combined organic layers were washed with Na2SO4Drying, filtration and concentration in vacuo gave the title compound (1.0g) as a bright yellow solid. Ms (esi): c21H27ClN4Theoretical value of O386; no measured value of quality was obtained.
Description 60
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide, dihydrochloride (D60)
Figure BDA0001212817760000461
To a solution of (S) -4- (5-chloro-3- (3-cyano-5-fluorobenzamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D46, 320mg) in methanol (20mL) was added HCl (46.6 mg). After stirring at 60 ℃ for 5 h, the mixture was concentrated to give the title compound (250mg) as a white solid. Ms (esi): c21H22ClFN4A theoretical value of O of 400; found value 401[ M + H]+。
Descriptions 61-64
Descriptions 61-64 were prepared using procedures similar to those described in description 60.
D61 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide, dihydrochloride
D62 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-cyano-5-fluoronicotinamide, dihydrochloride
D63 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide, dihydrochloride
D64 (S) -5-chloro-N- (5-cyano-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -6-methylnicotinamide, dihydrochloride
Figure BDA0001212817760000462
Description 65
(S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide, dihydrochloride (D65)
A mixture of (S) -tert-butyl 4- (5-chloro-3- (5-fluoronicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D45, 300mg) and HCl (2293mg) in 1, 4-dioxane (6mL) was stirred for 2 hours. The mixture was concentrated to give the title compound (210 mg). Ms (esi): c19H22ClFN4Theoretical value of O376; measured value 377[ M + H]+。
Description 66
(S) - (4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (D66)
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (484mg) in DCM (20mL) was added DMAP (46.0mg) and EDC (1307 mg). After stirring for 20min, a solution of (S) -1- (5-chloro-2-methyl-3-nitrobenzyl) -3-methylpiperazine (D32, 960mg) in DCM (5mL) was added. The resulting mixture was stirred overnight and washed with water (2X 15 mL). The organic layer was washed with Na2SO4Drying, filtration and concentration in vacuo gave the title compound (1.43 g). Ms (esi): c19H26ClN3O4Theoretical value 395; found 396[ M + H]+。
Description 67
((S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone (D67)
Figure BDA0001212817760000473
To a mixture of (R) -tetrahydrofuran-2-carboxylic acid (364mg), DIPEA (1215mg) and HATU (1783mg) in DMF (15mL) was added (S) -1- (5)-chloro-2-methyl-3-nitrobenzyl) -3-methylpiperazine (D32, 890 mg). The mixture was stirred at 25 ℃ for 6 hours. The resulting mixture was diluted with water (70mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with water (3 × 50mL) and brine (2 × 50mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (eluting with PE: EA ═ 3: 1) to give the title compound (1.2g) as a yellow oil. Ms (esi): c18H24ClN3O4Theoretical value 381; measured value 382[ M + H]+。
Descriptions 68 to 73
Descriptions 68-73 were prepared using procedures similar to those described in description 67.
D68 ((S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone
D69 ((S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone
D70 ((S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone
D71 ((S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone
D72 ((S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-ethylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone
D73 ((S) -4- (5-fluoro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone
Figure BDA0001212817760000491
Description 74
((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone (D74)
Figure BDA0001212817760000492
To a mixture of ((S) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone (D68, 1.2g), iron (0.877g) in methanol (15mL) was added a solution of ammonium chloride (0.841g) in water (3 mL). The mixture was stirred at 70 ℃ for 1 hour and then filtered. The filtrate was concentrated and the residue was dissolved in EA and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound (800mg) as a yellow solid. Ms (esi): c18H26ClN3O2A theoretical value 351; found value 352[ M + H]+。
Description of 75-80
Descriptions 75-80 were prepared using procedures analogous to those described in description 74.
D75 ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone
D76 ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone
D77 ((S) -4- (3-amino-5-fluoro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone
D78 ((S) -4- (3-amino-5-fluoro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone
D79 ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-ethylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone
D80 ((S) -4- (3-amino-5-fluoro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone
Figure BDA0001212817760000501
Description 81
(S) - (4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (D81)
Figure BDA0001212817760000502
To a solution of (S) - (4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (D66, 1.3g) in ethanol (20mL) was added tin (II) chloride dihydrate (3.70 g). The mixture was stirred at room temperature overnight and then concentrated. The residue was suspended in DCM (30 mL). Aqueous NaOH (2M) was added until a clear solution formed. The organic phase was separated. The aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated to give the title compound (1.09 g). Ms (esi): c19H28ClN3O2Theoretical value 365; found value of 366[ M + H]+。
Description 82
5-methoxy-6-methylnicotinic acid (D82)
Figure BDA0001212817760000511
A mixture of 5-fluoro-6-methylnicotinic acid (D17, 3.5g) and sodium methoxide (12.2g) in DMF (50mL) was heated to 140 ℃ for 16 hours. After cooling to room temperature, the mixture was filtered and the solid was collected. The solid was dissolved in water (10mL) at 0 ℃ and the pH was adjusted to 3-4 using HCl solution (2M). The precipitate was collected by filtration, washed with water and dried to give the title compound (2.45g) as a white solid. Ms (esi): c8H9NO3A theoretical value of 167; found value of 168[ M + H]+。
Description 83
(R) -4- (5-chloro-2-methyl-3-nitrobenzoyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (D83)
Figure BDA0001212817760000512
A suspension of 5-chloro-2-methyl-3-nitrobenzoic acid (D20, 5g) in thionyl chloride (20ml) was stirred and heated at reflux for 3 h. The mixture was concentrated in vacuo and the residue was added to (R) -tert-butyl 2-methylpiperazine-1-carboxylate (4.18g) and TEA (N)7.04g) in DCM (50 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with saturated NaHCO3The solution (50mL) and brine (2X 50mL) were washed, then Na2SO4After drying and filtration, the solvent was removed in vacuo to give the title compound (8g) as a white solid.
Description 84
Description 84 was prepared using a procedure similar to that described in description 27.
D84 (R) -4- (5-chloro-2-methyl-3-nitrobenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0001212817760000513
Figure BDA0001212817760000521
Description 85
Description 85 was prepared using similar procedures as described in description 74.
D85 (R) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0001212817760000522
Description of 86-87
Descriptions 86-87 were prepared using procedures analogous to those described in description 40, with the specific reaction solvents listed in the table.
D86 tert-butyl (S) -4- (5-chloro-3- (5, 6-dimethylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate
D87 (R) -4- (5-chloro-3- (5-fluoro-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0001212817760000523
Description 88
Description 88 is prepared using procedures analogous to those described in description 34.
D88 tert-butyl (S) -4- (5-chloro-3- (5-methoxy-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate
Figure BDA0001212817760000531
Description 89-91
Descriptions 89-91 were prepared using procedures analogous to those described in description 65.
D89 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide, dihydrochloride
D90 (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide, dihydrochloride
D91 (R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, dihydrochloride
Figure BDA0001212817760000532
Description 92
(R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, 2 trifluoroacetate (D92)
To a solution of (R) -tert-butyl 4- (5-chloro-3- (5-fluoro-6-methylnicotinamido) -2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D87, 814mg) in DCM (8mL) was added trifluoroacetic acid (1.3mL) dropwise at room temperature. The reaction mixture was stirred overnight. The solvent was removed in vacuo, the residue was dissolved in EtOAc (20mL) and saturated Na2CO3The solution was neutralized to pH 10. Extract, extract the aqueous layer three times with EtOAc (3X 10 mL). The combined organic layers were washed with Na2SO4And (5) drying. Filtration and concentration of the filtrate to dryness gave the title compound (950mg,19f NMR showed it to be a TFA salt).1H NMR(400MHz，MeOD-d4)：8.87(s，1H)，8.07(d，J＝9.8Hz，1H)，7.37(s，1H)，7.34(s，1H)，3.69(s，2H)，3.41-3.36(m，2H)，3.16(t，J＝12.0Hz，1H)，3.03(t，J＝12.8Hz，2H)，2.60(s，3H)，2.47(t，J＝12.3Hz，1H)，2.32-2.22(m，4H)，1.31(d，J＝6.6Hz，3H)。19F NMR(376MHz，MeOD-d4)：-77.3，-125.3。MS(ESI)：C20H24ClFN4Theoretical value of O390; found value 391[ M + H]+。
Description 93
5- (ethoxycarbonyl) -3-fluoro-2-methylpyridine 1-oxide (D93)
Figure BDA0001212817760000542
To a solution of ethyl 5-fluoro-6-methylnicotinate (prepared using a similar procedure as described for D16, 200mg) in DCM (5mL) was added 3-chlorobenzhydroperoxy acid (226mg) at 25 ℃ overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (PE/EA ═ 1/1) to afford the title compound (200mg) as a white solid. Ms (esi): c9H10FNO3A theoretical value of 199; measured value of 200[ M + H]+。
Description 94
5-carboxy-3-fluoro-2-methylpyridine 1-oxide (D94)
Figure BDA0001212817760000551
To a solution of 5- (ethoxycarbonyl) -3-fluoro-2-methylpyridine 1-oxide (D93, 200mg) in THF (2mL) at 25 ℃ was added water (2.000mL) and lithium hydroxide (72.1mg), and after the addition was complete, the reaction mixture was stirred at 25 ℃ for 1 h. The organic solvent was removed in vacuo, the aqueous layer was acidified to pH-3 with hydrogen chloride (1M aqueous solution) and extracted with ethyl acetate (30mL), the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (170mg) as a white solid. Ms (esi): c7H6FNO3A theoretical value 171; found value of 172[ M + H]+。
Description 95
(S) -5- ((3- ((4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl) methyl) -5-chloro-2-methylphenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide (D95)
Figure BDA0001212817760000552
To a solution of 5-carboxy-3-fluoro-2-methylpyridine 1-oxide (D94, 170mg) in DMF (5mL) at 25 ℃ were added HATU (378mg), DIPEA (0.174mL) and tert-butyl (S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazine-1-carboxylate (D30, 352mg), and the reaction mixture was stirred at 25 ℃ overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate-2/1) to give the title compound (300mg) as a yellow solid. Ms (esi): c25H32ClFN4O4A theoretical value 506; measured value 507[ M + H]+。
Description 96
(S) -5- ((5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide, dihydrochloride (D96)
Figure BDA0001212817760000561
To a solution of (S) -5- ((3- ((4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl) methyl) -5-chloro-2-methylphenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide (D95, 300mg) in 1, 4-dioxane (10mL) was added hydrogen chloride (108mg), and the reaction mixture was stirred at 25 ℃ for 1h, then filtered to give the title compound (280mg) as a yellow solid. Ms (esi): c20H24ClFN4O2A theoretical value 406; found value 407[ M + H]+。
Example 1
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E1)
Figure BDA0001212817760000562
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (1.896g) in DCM (20mL) was added 3 drops of DMF followed by dropwise addition of a solution of oxalyl chloride (1.403mL) in DCM (5mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in acetonitrile (10 mL). The resulting mixture was added dropwise to a mixture of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 4.65g) and potassium carbonate (5.04g) in acetonitrile (30mL) at 0 ℃. After addition, the reaction mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to dryness. The residue was dissolved in DCM (40mL) and saturated Na2CO3And (4) washing the solution. The organic layer was washed with Na2SO4Dried, filtered and concentrated. The residue was purified by column chromatography (eluting with DCM/MeOH, MeOH% ═ 0.5-2%) to give the crude product (5.2g) as a white solid, which was purified again by column chromatography and then by reverse phase chromatography. The pure fractions were collected and lyophilized to give the TFA salt of the title compound, which was dissolved in DCM (30mL) and washed with NaOH solution (0.6g in 40mL of water) and water (20 mL). The organic layer was concentrated to dryness. The residue was dissolved in acetonitrile/water and lyophilized again to give the title compound (1.9g) as a white solid.1HNMR(400MHz，MeOD-d4)：8.32(s，1H)，8.25(d，J＝7.6Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.71(t，J＝7.8Hz，1H)，7.36(brs，1H)，7.29(brs，1H)，4.74-4.59(m，0.5H)，4.38-4.19(m，1H)，4.00-3.88(m，2H)，3.88-3.75(m，0.5H)，3.61-3.34(m，4.5H)，3.02-2.63(m，3.5H)，2.30(s，3H)，2.24-1.93(m，2H)，1.91-1.49(m，4H)，1.42-1.14(m，3H)。MS(ESI)：C27H31ClN4O3Theoretical value 494; found value of 495[ M + H]+。
Example 2
3-cyano-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide, trifluoroacetate (E2)
To a solution of (S) -3-cyano-N- (5-fluoro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) benzamide (D50, 109.7mg) and (R) -tetrahydrofuran-2-carboxylic acid (40.9mg) in DCM (5mL) was added EDC (116.4mg) and HOBt (60.7 mg). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (10mL) and washed with water (10 mL). The organic layer was concentrated to dryness and the residue was purified by MDAP (acidic conditions) to give the title compound (65.9mg) as a white solid.1H NMR(400MHz，MeOD-d4)：8.34(s，1H)，8.28(d，J＝7.8Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.75(t，J＝7.8Hz，1H)，7.40-7.32(m，2H)，4.77-4.55(m，2H)，4.47(brs，2H)，4.26(d，J＝13.7Hz，0.5H)，3.98-3.79(m，2H)，3.66-3.39(m，2.5H)，3.29-2.97(m，3H)，2.34(s，3H)，2.25-2.05(m，2H)，2.00-1.90(m，2H)，1.54-1.24(m，3H)。19F NMR(376MHz，MeOD-d4)：-76.6，-116.0。MS(ESI)：C26H29FN4O3Theoretical value 464; found value of 465[ M + H]+。
Example 3
3-cyano-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide, trifluoroacetate (E3)
Figure BDA0001212817760000581
Example 3 was prepared using a procedure similar to that described in example 2.1H NMR(400MHz，MeOD-d4)：8.34(s，1H)，8.28(d，J＝8.1Hz，1H)，7.99(d，J＝7.8Hz，1H)，7.75(t，J＝7.8Hz，1H)，7.40-7.31(m，2H)，4.82-4.75(m，0.5H)，4.70(t，J＝6.7Hz，1H)，4.61(brs，0.5H)，4.52-4.39(m，2H)，4.32-4.15(m，0.5H)，3.95-3.80(m，2H)，3.61(brs，0.5H)，3.55-3.40(m，2H)，3.28-3.00(m，3H)，2.33(s，3H)，2.23-2.07(m，2H)，2.02-1.89(m，2H)，1.54-1.25(m，3H)。19F NMR(376MHz，MeOD-d4)：-76.6，-116.1。MS(ESI)：C26H29FN4O3Theoretical value 464; found value of 465[ M + H]+。
Example 4
(S) -3-cyano-N- (5-fluoro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide (E4)
Figure BDA0001212817760000582
To a mixture of (S) -3-cyano-N- (5-fluoro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) benzamide (D50, 240mg) in DMF (5mL) was added HATU (374mg) at room temperature. The mixture was stirred at 25 ℃ for 10min, then DIPEA (169mg) was added. The mixture was stirred at 25 ℃ overnight. After cooling, the mixture is extracted with EA. The organic phase was washed with Na2SO4Dried, filtered through a pad of thin celite and concentrated to give a brown oil which was purified by column chromatography (eluting with PE: EA ═ 10: 1) to give a colourless oil which was purified by reverse phase chromatography (C18, mobile phase 0.01% NH4HCO3:H2O，CH3CN, 10-95%, 9.5min,30mL/min) to give a pale yellow solid (250mg) which was purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH4HCO3:H2O，CH3CN, 50-95%, 9.0min, 30mL/min) to give the title compound (110mg) as a white solid.1H NMR(400MHz，CDCl3)：8.20(s，1H)，8.16(d，J＝7.8Hz，1H)，7.94-7.82(m，2H)，7.68(t，J＝7.8Hz，1H)，7.62(d，J＝8.5Hz，1H)，6.95(d，J＝6.5Hz，1H)，4.76(brs，0.5H)，4.38(d，J＝13.3Hz，0.5H)，4.11-3.96(m，2.5H)，3.63(d，J＝12.0Hz，0.5H)，3.53-3.33(m，4.5H)，2.98-2.87(m，0.5H)，2.84-2.75(m，1H)，2.75-2.62(m，2H)，2.31(s，3H)，2.25-2.15(m，1H)，2.09-1.79(m，3H)，1.70-1.52(m，2H)，1.42-1.18(m，3H)。MS(ESI)：C27H31FN4O3A theoretical value of 478; found value of 479[ M + H]+。
Examples 5 to 21
Examples 5-21 were prepared using procedures analogous to those described in example 4, with the specific reaction bases or solvents listed in the table below.
E5 3-cyano-N- (5-fluoro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide
E6 3-cyano-N- (5-fluoro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide
E7N- (5-chloro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide
E8N- (5-chloro-2-methyl-3- (((3S) -3-methyl-4- (tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide
E9 (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide
E10N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide
E11N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide
E12N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide
E13 (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E14N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-ethylnicotinamide
E15N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide
E16N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide
E17 (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide
E18N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide
E19N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-methylnicotinamide
E20N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-fluoronicotinamide
E21N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyano-5-fluoronicotinamide
Figure BDA0001212817760000601
Figure BDA0001212817760000611
Figure BDA0001212817760000621
Figure BDA0001212817760000631
Figure BDA0001212817760000641
Example 22
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide (E22)
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide, dihydrochloride (D60, 150mg) in DCM (20mL) was added (R) -tetrahydrofuran-2-carboxylic acid (43.4mg), HATU (142mg) and DIPEA (0.065 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH)4HCO3/H2O，CH3CN, 50-95%, 9.0min, 30mL/min) to give the title compound (100mg) as a white solid.1H NMR(400MHz，CDCl3)：8.16(brs，0.5H)，8.04-8.02(m，1.5H)，7.94(t，J＝8.2Hz 1H)，7.69(s，1H)，7.58(d，J＝6.8Hz，1H)，7.19(d，J＝7.3Hz，1H)，4.68-4.61(m，1H)，4.58-4.55(m，0.5H)，4.24-4.13(m，1H)，3.98-3.93(m，1H)，3.89-3.81(m，1.5H)，3.48-3.26(m，2.5H)，2.88-2.72(m，1H)，2.69-2.63(m，1H)，2.57(d，J＝11.3Hz，0.5H)，2.30(s，3H)，2.24-1.87(m，6H)，1.36-1.17(m，3H)。MS(ESI)：C26H28ClFN4O3Theoretical value 498; found 499[ M + H]+。
Example 23
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide (E23)
Figure BDA0001212817760000651
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide, dihydrochloride (D60, 100mg) in DCM (20mL) was added (S) -tetrahydrofuran-2-carboxylic acid (29.0mg), HATU (114mg) and DIPEA (0.131 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH)4HCO3/H2O，CH3CN, 50-95%, 9.0min, 30mL/min) gave the title compound (54mg) as a white solidAnd (3) a body.1H NMR(400MHz，CDCl3)：7.99(brs，1H)，7.91(brs，1.5H)，7.82-7.72(m，1.5H)，7.58(d，J＝7.3Hz，1H)，7.20(d，J＝2.0Hz，1H)，4.73-4.65(m，0.5H)，4.57(brs，1H)，4.40-4.25(m，1H)，3.97-3.91(m，1H)，3.88-3.83(m，1H)，3.78-3.70(m，0.5H)，3.48-3.36(m，2.5H)，2.94-2.85(m，0.5H)，2.80-2.61(m，2H)，2.35-2.15(m，5H)，2.10-1.86(m，4H)，1.34-1.22(m，3H)。MS(ESI)：C26H28ClFN4O3Theoretical value 498; found 499[ M + H]+。
Example 24
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E24)
Figure BDA0001212817760000661
To a mixture of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 200mg) in DMF (5mL) was added HATU (298mg) at room temperature. The mixture was stirred at 25 ℃ for 10min, then DIPEA (135mg) was added. The mixture was stirred at 25 ℃ overnight. The mixture was partitioned between water and EA. The organic phase was washed with Na2SO4Dried, filtered through a thin pad of celite and concentrated to give a brown oil which is purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH)4HCO3/H2O，CH3CN, 50-95%, 9.0min, 30mL/min) to give the title compound (50mg) as a white solid.1H NMR(400MHz，DMSO-d6)：10.19(s，1H)，8.40(s，1H)，8.26(d，J＝7.8Hz，1H)，8.08(d，J＝7.8Hz，1H)，7.76(t，J＝7.8Hz，1H)，7.39(d，J＝1.5Hz，1H)，7.29-7.27(m，1H)，4.67-4.59(m，1H)，4.54-4.45(m，0.5H)，4.24-4.11(m，1H)，3.83-3.70(m，2.5H)，3.49-3.40(m，2H)，3.23-3.12(m，0.5H)，2.85-2.72(m，1.5H)，2.64(d，J＝11.3Hz，1H)，2.22(s，3H)，2.18-1.75(m，6H)，1.28-1.11(m，3H)。MS(ESI)：C26H29ClN4O3A theoretical value of 480; found 481[ M + H]+。
Example 25
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E25)
Figure BDA0001212817760000662
To a mixture of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 200mg) in DMF (5mL) was added HATU (298mg) at room temperature. The mixture was stirred at 25 ℃ for 10min, then DIPEA (135mg) was added. The mixture was stirred at 25 ℃ overnight. The resulting mixture was partitioned between water and EA. The organic phase was washed with Na2SO4Dried, filtered through a thin pad of celite and concentrated to give a brown oil which is purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH)4HCO3/H2O，CH3CN, 50-95%, 9.0min, 30mL/min) to give the title compound (60mg) as a white solid.1H NMR(400MHz，DMSO-d6)：10.19(s，1H)，8.41(s，1H)，8.26(d，J＝7.8Hz，1H)，8.08(d，J＝7.8Hz，1H)，7.76(t，J＝7.8Hz，1H)，7.39(d，J＝2.0Hz，1H)，7.28(brs，1H)，4.56(brs，0.5H)，4.22-4.19(m，1H)，3.96-3.92(m，0.5H)，3.85-3.60(m，4H)，3.50-3.43(m，2H)，3.34-3.27(m，1H)，3.22-3.16(m，0.5H)，2.84-2.74(m，1.5H)，2.65(d，J＝11.3Hz，1H)，2.22(s，3H)，2.16-1.90(m，4H)，1.27-1.11(m，3H)。MS(ESI)：C26H29ClN4O3A theoretical value of 480; found 481[ M + H]+。
Example 26
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E26)
Figure BDA0001212817760000671
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 600mg) in DMF (50mL) was added (S) -tetrahydrofuran-2-carboxylic acid (110mg), HATU (1192mg) and DIPEA (0.547 mL). The mixture was stirred at room temperature for 2 hours. Water was added. The solution was extracted with EA (3X 50 mL). The filtrate was taken up with saturated NaHCO3The solution, water and brine were washed. The resulting mixture was washed with MgSO4And (5) drying. After filtration, the residue was purified by preparative HPLC to give the title compound (50mg) as a white solid.1H NMR(400MHz，CDCl3)：8.22(s，1H)，8.17(d，J＝7.5Hz，1H)，8.06-7.96(m，1H)，7.86(d，J＝7.8Hz，1H)，7.75(brs，1H)，7.66(t，J＝7.9Hz，1H)，7.18(d，J＝2.0Hz，1H)，4.67(brs，0.5H)，4.57(t，J＝6.1Hz，1H)，4.36(brs，0.5H)，4.31-4.22(m，0.5H)，3.95-3.90(m，1H)，3.87-3.82(m，1H)，3.77-3.68(m，0.5H)，3.47-3.39(m，2.5H)，2.95-2.84(m，0.5H)，2.81-2.59(m，2H)，2.35-2.15(m，5H)，2.10-1.85(m，4H)，1.33-1.21(m，3H)。MS(ESI)：C26H29ClN4O3A theoretical value of 480; found 481[ M + H]+。
Example 27
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E27)
Figure BDA0001212817760000681
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 150mg) in DMF (50mL) was added (S) -tetrahydrofuran-3-carboxylic acid (54.6mg), HATU (149mg) and DIPEA (0.137 mL). The mixture was stirred at room temperature for 2 hours. Water was added. The solution was extracted with EA (3X 50 mL). The filtrate was taken up with saturated NaHCO3The solution, water and brine were washed. The resulting solution was diluted with MgSO4And (5) drying. After filtration, the residue was purified by chiral preparative HPLC to give the title compound (20mg) as a white solid.1H NMR(400MHz，CDCl3)：8.19(s，1H)，8.15(d，J＝7.8Hz，1H)，7.89(d，J＝7.8Hz，1H)，7.82(brs，1H)，7.76(d，J＝7.5Hz，1H)，7.68(t，J＝7.8Hz，1H)，7.18(d，J＝2.0Hz，1H)，4.77(brs，0.5H)，4.39(d，J＝14.1Hz，0.5H)，4.07-3.79(m，4.5H)，3.64(d，J＝13.6Hz，0.5H)，3.52-3.32(m，2.5H)，3.27-3.14(m，1H)，2.98-2.66(m，2.5H)，2.32(s，3H)，2.26-2.00(m，4H)，1.36-1.22(m，3H)。MS(ESI)：C26H29ClN4O3A theoretical value of 480; found 481[ M + H]+。
Example 28
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide (E28)
Figure BDA0001212817760000682
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide (D53, 96.5mg) and (R) -tetrahydrofuran-2-carboxylic acid (36.5mg) in anhydrous DMF (5mL) was added HATU (182.3mg) and DIPEA (0.126 mL). The reaction mixture was stirred overnight and then directly purified with MDAP (basic conditions) to give the title compound (65.9mg) as a white solid.1H NMR(400MHz，MeOD-d4)：8.39(dd，J＝5.9Hz，2.0Hz，1H)，8.34-8.30(m，1H)，7.54(t，J＝8.9Hz，1H)，7.34(s，1H)，7.30(brs，1H)，4.75-4.67(m，1H)，4.66-4.55(m，1.5H)，4.27(d，J＝13.4Hz，0.5H)，4.22-4.14(m，0.5H)，4.00-3.90(m，1H)，3.89-3.78(m，1.5H)，3.55-3.45(m，2H)，3.39-3.33(m，0.5H)，3.05-2.96(m，0.5H)，2.89-2.78(m，1H)，2.77-2.69(m，1H)，2.30(s，3H)，2.27-2.07(m，3H)，2.02-1.87(m，3H)，1.38-1.23(m，3H)。19F NMR(376MHz，MeOD-d4)：-105.1。MS(ESI)：C26H28ClFN4O3Theoretical value 498; found 499[ M + H]+。
Example 29
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide (E29)
Figure BDA0001212817760000691
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide (D53, 99.8mg) and (S) -tetrahydrofuran-2-carboxylic acid (39.6mg) in anhydrous DMF (5mL) was added HATU (189.3mg) and DIPEA (0.130 mL). The mixture was stirred overnight and then directly purified with MDAP (basic conditions) to give the title compound (68.9mg) as a white solid.1H NMR(400MHz，MeOD-d4)：8.39(dd，J＝6.1Hz，2.0Hz，1H)，8.36-8.29(m，1H)，7.54(t，J＝8.8Hz，1H)，7.35(d，J＝2.0Hz，1H)，7.31(d，J＝2.0Hz，1H)，4.75-4.53(m，2.5H)，4.39-4.24(m，1H)，3.97-3.89(m，1H)，3.88-3.80(m，1H)，3.76(d，J＝13.7Hz，0.5H)，3.57-3.45(m，2H)，3.45-3.36(m，0.5H)，3.07-2.93(m，0.5H)，2.84(d，J＝10.8Hz，1H)，2.72(d，J＝11.5Hz，1H)，2.30(s，3H)，2.27-1.87(m，6H)，1.42-1.21(m，3H)。19F NMR(376MHz，MeOD-d4)：-106.7。MS(ESI)：C26H28ClFN4O3Theoretical value 498; found 499[ M + H]+。
Example 30
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E30)
Figure BDA0001212817760000701
To a solution of (R) -tetrahydrofuran-2-carboxylic acid (44.6mg), (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (D55, 150mg) and DIPEA (0.201mL) in DCM (10mL) was added HATU (175mg) at 0 ℃. The mixture was stirred at room temperature overnight and then with NaHCO3The aqueous solution and brine were washed three times. Subjecting the obtained solution toNa2SO4Dried, filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (34mg) as a white solid.1H NMR(400MHz，DMSO-d6)：10.19(s，1H)，8.89(s，1H)，8.12(d，J＝10.0Hz，1H)，7.39(s，1H)，7.29(d，J＝4.8Hz，1H)，4.68-4.58(m，1H)，4.55-4.47(m，0.5H)，4.24-4.12(m，1H)，3.85-3.69(m，2.5H)，3.51-3.41(m，2H)，3.22-3.13(m，0.5H)，2.86-2.69(m，1.5H)，2.64(d，J＝11.0Hz，1H)，2.54(d，J＝2.8Hz，3H)，2.22(s，3H)，2.18-1.73(m，6H)，1.29-1.12(m，3H)。19F NMR(376MHz，DMSO-d6)：-124.7。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 31
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E31)
To a solution of (S) -tetrahydrofuran-2-carboxylic acid (44.6mg), (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (D55, 150mg) and DIPEA (0.201mL) in DCM (10mL) was added HATU (175mg) at 0 ℃. The mixture was stirred at room temperature overnight and then with NaHCO3The aqueous solution and brine were washed three times. The obtained solution was treated with Na2SO4Dried, filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (31mg) as a white solid.1H NMR(400MHz，DMSO-d6)：10.19(s，1H)，8.89(s，1H)，8.12(d，J＝10.0Hz，1H)，7.39(d，J＝2.0Hz，1H)，7.28(d，J＝1.8Hz，1H)，4.59(t，J＝6.5Hz，1H)，4.56-4.46(m，0.5H)，4.37-4.26(m，0.5H)，4.16(d，J＝12.0Hz，0.5H)，3.85-3.67(m，2.5H)，3.52-3.38(m，2H)，3.28-3.14(m，0.5H)，2.89-2.70(m，1.5H)，2.64(d，J＝10.8Hz，1H)，2.54(d，J＝2.8Hz，3H)，2.30-2.14(m，4H)，2.05-1.73(m，5H)，1.32-1.06(m，3H)。19F NMR(376MHz，DMSO-d6)：-124.7。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 32
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (E32)
Figure BDA0001212817760000711
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (D57, 95.0mg) and (R) -tetrahydrofuran-2-carboxylic acid (40.5mg) in anhydrous DMF (5mL) was added HATU (182.8mg) and DIPEA (0.13 mL). The mixture was stirred at room temperature overnight and then directly purified with MDAP (basic conditions, ACN/H)2O (containing 0.05% NH)3H2O), ACN% ═ 30-70%), to give the title compound (78.5mg) as a white solid.1H NMR(400MHz，MeOD-d4)：9.21(s，1H)，8.64(s，1H)，7.44(brs，2H)，4.79-4.62(m，1.5H)，4.60-4.11(m，2H)，3.99-3.79(m，2.5H)，3.76-3.35(m，2.5H)，3.24-2.96(m，1.5H)，2.94-2.67(m，4H)，2.33(s，3H)，2.27-1.78(m，5H)，1.52-1.13(m，3H)。MS(ESI)：C26H30ClN5O3Theoretical value 495; measured value 496[ M + H]+。
Example 33
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (E33)
Figure BDA0001212817760000721
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (D57, 95.6mg) and (S) -tetrahydrofuran-2-carboxylic acid (40.0mg) in anhydrous DMF (5mL) was added HATU (176.3mg) and DIPEA (0.13 mL). The mixture was stirred at room temperature overnight and then directly purified with MDAP (basic conditions, ACN/H)2O (containing 0.05% NH)3H2O), ACN% ═ 30-70%), to give the title compound (75.9mg) as a white solid.1H NMR(400MHz，MeOD-d4)：9.21(s，1H)，8.64(s，1H)，7.43(brs，2H)，4.76-4.60(m，1.5H)，4.58-4.11(m，2H)，3.96-3.77(m，2.5H)，3.75-3.36(m，2.5H)，3.21-2.96(m，1.5H)，2.93-2.60(m，4H)，2.33(s，3H)，2.25-1.83(m，5H)，1.51-1.13(m，3H)。MS(ESI)：C26H30ClN5O3Theoretical value 495; measured value 496[ M + H]+。
Example 34&35
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (E34& E35)
To a mixture of 2-methyltetrahydrofuran-2-carboxylic acid (52.1mg) and (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -3-cyanobenzamide (D52, 153mg) in DMF (6mL) was added HATU (228mg) at room temperature. After stirring for 10min, DIPEA (0.105mL) was added. The mixture was stirred at 50 ℃ for 18 hours. The resulting mixture was diluted with water (10mL) and then extracted with EA (30 mL). The organic phase was washed with Na2SO4Dried, filtered and concentrated to give a brown oil. The residue was purified by preparative HPLC (Gilson GX-281, mobile phase: 0.01% NH)4HCO3/H2O，CH3CN, 50-95%, 9.0min, 30mL/min) to give the crude product (150mg) as a white solid, which was purified by preparative chiral HPLC (column: AD-H4.6X 250mm, 5 um; co-solvent: MeOH (0.1% DEA); the column temperature was 39.9 ℃; CO 22Flow rate: 2.25 mL/min; flow rate of co-solvent: 0.75 mL/min; co-solvent: 25%) to obtain the titleCompound (50mg and 65mg) as a white solid. Isomer 1:1H NMR(400MHz，CDCl3)：8.21(brs，1H)，8.16(d，J＝8.0Hz，1H)，7.87(d，J＝7.8Hz，1H)，7.82-7.75(m，1H)，7.67(t，J＝7.8Hz，1H)，7.22-7.15(m，1H)，5.18-5.06(m，0.5H)，4.82-4.68(m，0.5H)，4.49(d，J＝13.8Hz，0.5H)，4.29-4.18(m，0.5H)，4.08-3.87(m，1H)，3.87-3.64(m，1H)，3.46-3.30(m，2.5H)，3.00-2.67(m，2.5H)，2.61(d，J＝11.3Hz，1H)，2.31(s，3H)，2.27-2.13(m，1H)，2.07-1.77(m，3H)，1.68-1.53(m，2H)，1.50-1.41(m，3H)，1.38-1.15(m，3H)。MS(ESI)：C27H31ClN4O3theoretical value 494; found value of 495[ M + H]+. Isomer 2:1H NMR(400MHz，CDCl3)：8.20(brs，1H)，8.16(d，J＝7.8Hz，1H)，7.87(d，J＝7.8Hz，1H)，7.83-7.76(m，1H)，7.67(t，J＝7.8Hz，1H)，7.18(s，1H)，4.90-4.80(m，0.5H)，4.72(d，J＝12.5Hz，0.5H)，4.67-4.57(m，0.5H)，4.38-4.29(m，0.5H)，3.99-3.91(m，1H)，3.85-3.72(m，1H)，3.48-3.32(m，2H)，3.27-3.15(m，0.5H)，2.96-2.81(m，1.5H)，2.80-2.59(m，2H)，2.32(s，3H)，2.23-1.78(m，4H)，1.70-1.55(m，2H)，1.51-1.38(m，3H)，1.37-1.17(m，3H)。MS(ESI)：C27H31ClN4O3theoretical value 494; found value of 495[ M + H]+。
Examples 36 to 55
Examples 36-55 were prepared using procedures analogous to those described in examples 34&35, with the specific reaction bases or solvents listed in the table below.
E36& E37: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E38& E39: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -2-methyltetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E40& E41: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide
E42& E43: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide
E44& E45: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide
E46& E47: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoronicotinamide
E48& E49: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide
E50& E51: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -2-methylthiazole-5-carboxamide
E52& E53: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E54& E55: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydro-2H-pyran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
Figure BDA0001212817760000741
Figure BDA0001212817760000761
Figure BDA0001212817760000771
Figure BDA0001212817760000781
Figure BDA0001212817760000791
Example 56&57
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E56)
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E57)
HATU (438mg), DIPEA (0.402mL),A mixture of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (D55, 300mg) and tetrahydrofuran-3-carboxylic acid (89mg) in DCM (150mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by preparative HPLC to give the crude product (260mg), which was isolated by chiral HPLC to give the title compounds (E56(55mg) and E57(50mg)) as white solids. E56: chiral SFC: column: OJ-H, 4.6X 250mm, 5 um; co-solvent: MeOH (containing 0.1% DEA); column temperature: 36.7 ℃; CO 22Flow rate: 2.4 mL/min; flow rate of co-solvent: 0.6 mL/min; co-solvent: 20 percent; t is tR＝7.40min。1H NMR(400MHz，MeOD-d4)：8.88(s，1H)，8.08(d，J＝9.6Hz，1H)，7.37(d，J＝2.0Hz，1H)，7.32(s，1H)，4.68(brs，0.5H)，4.34-4.31(m，0.5H)，4.25(brs，0.5H)，4.04-3.99(m，0.5H)，3.96-3.77(m，4H)，3.56-3.36(m，3.5H)，3.05-2.97(m，0.5H)，2.88-2.83(m，1H)，2.80-2.75(m，1H)，2.61(brs，3H)，2.32(s，3H)，2.24-2.00(m，4H)，1.32-1.28(m，3H)。19F NMR(376MHz，MeOD-d4)：-125.4。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+. E57 chiral SFC column: OJ-H, 4.6X 250mm, 5 um; co-solvent: MeOH (containing 0.1% DEA); column temperature: 40 ℃; CO 22Flow rate: 2.4 mL/min; flow rate of co-solvent: 0.6 mL/min; co-solvent: 20 percent; t is tR＝8.51min。1H NMR(400MHz，MeOD-d4)：8.88(s，1H)，8.08(d，J＝9.6Hz，1H)，7.37(d，J＝2.0Hz，1H)，7.32(s，1H)，4.67(brs，0.5H)，4.34-4.31(m，1H)，3.98-3.78(m，4.5H)，3.53-3.48(m，2H)，3.43-3.41(m，1.5H)，2.99-2.85(m，0.5H)，2.88-2.85(m，1H)，2.80-2.75(m，1H)，2.61(brs，3H)，2.32(s，3H)，2.24-2.00(m，4H)，1.32-1.28(m，3H)。19FNMR(376MHz，MeOD-d4)：-125.4。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 58
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluorobenzamide (E58)
To a mixture of ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone (D75, 100mg), DMAP (38.2mg) in DCM (10mL) was slowly added 3-fluorobenzoyl chloride (45.1 mg). The mixture was stirred at 20 ℃ for 16 hours. The solvent was removed. The residue was purified by preparative HPLC to give the title compound (63mg) as a white solid.1HNMR(400MHz，MeOD-d4)：7.83-7.81(d，J＝8.4Hz，1H)，7.74-7.71(d，J＝12.0Hz，1H)，7.60-7.55(m，1H)，7.40-7.32(m，3H)，4.74-4.70(m，1H)，4.66-4.64(m，0.5H)，4.31-4.28(brs，0.5H)，4.25-4.15(m，0.5H)，4.00-3.82(m，2.5H)，3.56-3.48(m，2H)，3.39-3.33(m，0.5H)，3.06-2.99(m，0.5H)，2.89-2.78(m，1H)，2.77-2.74(m，1H)，2.32(s，3H)，2.27-1.94(m，6H)，1.40-1.25(m，3H)。MS(ESI)：C25H29ClFN3O3A theoretical value of 473; found 474[ M + H]+。
Examples 59 to 65
Examples 59-65 were prepared using procedures analogous to those described for example 58.
E59: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluorobenzamide
E60: 3-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide
E61: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-4-methylbenzamide
E62: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-4-methylbenzamide
E63: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3, 5-difluorobenzamide
E64: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3, 5-difluorobenzamide
E65: 3-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) benzamide
Figure BDA0001212817760000831
Example 66
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-5-methylbenzamide (E66)
A mixture of 3-fluoro-5-methylbenzoic acid (65.7mg) in thionyl chloride (338mg) was stirred at 80 ℃ for 1 hour. The mixture was then concentrated in vacuo. The residue was added to a mixture of ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone (D75, 100mg), DMAP (38.2mg) in DCM (8 mL). The mixture was stirred at 20 ℃ for 16 hours and then concentrated. The residue was purified by preparative HPLC and chiral HPLC to give the title compound (5mg) as a white solid.1H NMR(400MHz，MeOD-d4)：7.66(s，1H)，7.50(d，J＝9.6Hz，1H)，7.35-7.31(m，2H)，7.21(d，J＝9.0Hz，1H)，4.76-4.63(m，1.5H)，4.40-4.30(m，1H)，3.98-3.70(m，2.5H)，3.54-3.46(m，2H)，3.37-3.31(m，0.5H)，3.04-2.97(m，0.5H)，2.95-2.73(m，2H)，2.46(s，3H)，2.29(s，3H)，2.25-1.90(m，6H)，1.41-1.17(m，3H)。MS(ESI)：C26H31ClFN3O3Theoretical value 487; found 488[ M + H]+。
Example 67
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-fluoro-5-methylbenzamide (E67)
Figure BDA0001212817760000851
Example 67 was prepared using a procedure similar to that described in example 66.1H NMR(400MHz，MeOD-d4)：7.65(s，1H)，7.50(d，J＝9.6Hz，1H)，7.32(d，J＝9.6Hz，2H)，7.21(d，J＝9.0Hz，1H)，4.76-4.60(m，1.5H)，4.39-4.27(m，1H)，3.98-3.70(m，2.5H)，3.54-3.46(m，2H)，3.37-3.31(m，0.5H)，3.04-2.96(m，0.5H)，2.87-2.62(m，2H)，2.46(s，3H)，2.29(s，3H)，2.25-1.88(m，6H)，1.37-1.13(m，3H)。MS(ESI)：C26H31ClFN3O3Theoretical value 487; found 488[ M + H]+。
Example 68
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide (E68)
Figure BDA0001212817760000852
To a solution of 5, 6-dimethylnicotinic acid (D3, 55mg) and 1 drop of DMF in DCM (5mL) was added oxalyl chloride (0.080mL) dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was dissolved in DCM (5mL), to which was added ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone (D75, 128mg) and DIPEA (0.191 mL). The resulting mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The crude product was purified by preparative TLC (eluting with PE: EA ═ 1: 3) to give an oil. The oil was purified by preparative HPLC to give the title compound (20mg) as a white solidA colored solid.1H NMR(400MHz，MeOD-d4)：8.84(s，1H)，8.14(s，1H)，7.36(s，1H)，7.32(d，J＝1.6Hz，1H)，4.75-4.70(m，1H)，4.69-4.62(m，0.5H)，4.33-4.26(d，0.5H)，4.22-4.18(m，0.5H)，3.98-3.94(m，1H)，3.89-3.82(m，1.5H)，3.56-3.49(m，2H)，3.36-3.34(m，0.5H)，3.03-2.98(m，0.5H)，2.90-2.84(m，1H)，2.77-2.74(m，1H)，2.61(s，3H)，2.44(s，3H)，2.32(s，3H)，2.29-1.94(m，6H)，1.40-1.25(m，3H)。MS(ESI)：C26H33ClN4O3Theoretical value 484; measured value 485[ M + H]+。
Examples 69 to 72
Examples 69-72 were prepared using procedures analogous to those described for example 68, with the specific reaction bases listed in the table.
E69: n- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide
E70: n- (5-chloro-3- (((S) -3-ethyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) -2-methylphenyl) -5-fluoro-6-methylnicotinamide
E71: 5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) nicotinamide, trifluoroacetate salt
E72: 5-fluoro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
Figure BDA0001212817760000861
Figure BDA0001212817760000871
Example 73&74
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide & N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide (E73& E74)
Figure BDA0001212817760000872
A mixture of 5, 6-dimethylnicotinic acid (D3, 0.129g) in oxalyl chloride (3.07mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was added to a mixture of ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone (D76, 200mg) and DIPEA (0.147g) in DCM (20 mL). The mixture was stirred at 20 ℃ for 16 hours and then concentrated. The resulting mixture was purified by preparative HPLC and chiral HPLC to give the title compound (10mg and 8mg) as a white solid. Isomer 1:1H NMR(400MHz，MeOD-d4)：8.82(d，J＝2.0Hz，1H)，8.12(d，J＝1.2Hz，1H)，7.35(d，J＝2.4Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.67(brs，0.5H)，4.33-4.24(m，1H)，4.04-4.00(0.5H)，3.95-3.76(m，4H)，3.55-3.34(m，3.5H)，3.03-2.96(m，0.5H)，2.86(d，J＝11.6Hz，1H)，2.77-2.72(m，1H)，2.59(s，3H)，2.42(s，3H)，2.31(s，3H)，2.24-1.98(m，4H)，1.38-1.23(m，3H)。MS(ESI)：C26H33ClN4O3theoretical value 484; measured value 485[ M + H]+. Isomer 2:1H NMR(400MHz，MeOD-d4)：8.82(d，J＝1.6Hz，1H)，8.12(d，J＝1.2Hz，1H)，7.35(d，J＝2.0Hz，1H)，7.31(s，1H)，4.66(brs，0.5H)，4.34-4.30(m，1H)，3.97-3.75(m，4.5H)，3.56-3.37(m，3.5H)，3.03-2.95(m，0.5H)，2.86(d，J＝11.6Hz，1H)，2.78-2.72(m，1H)，2.59(s，3H)，2.42(s，3H)，2.31(s，3H)，2.26-1.98(m，4H)，1.36-1.24(m，3H)。MS(ESI)：C26H33ClN4O3theoretical value 484; measured value 485[ M + H]+。
Example 75&76
5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide & 5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide (E75& E76)
Figure BDA0001212817760000881
To a solution of 5-chloro-6-methylnicotinic acid (D5, 400mg) in DCM (2mL) was carefully added oxalyl chloride (0.612 mL). The mixture was stirred for 0.5 h, then concentrated to give 5-chloro-6-methylnicotinoyl chloride (500 mg). A portion of the residue (113mg) was added to a solution of ((S) -4- (3-amino-5-fluoro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydrofuran-3-yl) methanone (D80, 200mg) and DMAP (219mg) in DCM (3 mL). The mixture was stirred for 2 hours and then filtered. After concentration, water was added. The resulting mixture was extracted with EA. The organic phase was dried, concentrated and purified by preparative HPLC to give the title compound (6mg and 12 mg). Isomer 1:1H NMR(400MHz，MeOD-d4)：8.94(d，J＝1.2Hz，1H)，8.36(d，J＝1.6Hz，1H)，7.14-7.08(m，2H)，4.67(m，0.5H)，4.33-4.24(m，1H)，4.04-4.00(m，0.5H)，3.95-3.76(m，4H)，3.56-3.35(m，3.5H)，3.04-2.97(m，0.5H)，2.87(d，J＝11.2Hz，1H)，2.78-2.73(m，1H)，2.70(s，3H)，2.29(s，3H)，2.25-1.98(m，4H)，1.39-1.24(m，3H)。MS(ESI)：C25H30ClFN4O3a theoretical value 488; found 489[ M + H ]]+. Isomer 2:1H NMR(400MHz，MeOD-d4)：8.94(d，J＝1.2Hz，1H)，8.36(d，J＝1.2Hz，1H)，7.14-7.08(m，2H)，4.66(m，0.5H)，4.33-4.31(m，1H)，3.97-3.75(m，4.5H)，3.56-3.37(m，3.5H)，3.03-2.95(m，0.5H)，2.87(d，J＝11.6Hz，1H)，2.79-2.73(m，1H)，2.70(s，3H)，2.29(s，3H)，2.27-1.98(m，4H)，1.37-1.24(m，3H)。MS(ESI)：C25H30ClFN4O3a theoretical value 488; found 489[ M + H ]]+。
Example 77
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-cyanonicotinamide (E77)
Figure BDA0001212817760000891
To a solution of (S) - (4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (D81, 112.7mg) and 6-cyanonicotinic acid (51.7mg) in anhydrous DMF (5mL) was added HATU (178.7mg) and DIPEA (0.161 mL). The mixture was stirred at room temperature overnight and purified with MDAP (basic conditions, ACN/H)2O (containing 0.05% NH)3H2O), ACN% ═ 30% to 80%) to give the title compound (40.7mg) as an off-white solid.1HNMR(400MHz，MeOD-d4)：9.23(s，1H)，8.50(dd，J＝8.1Hz，1.7Hz，1H)，8.04(d，J＝8.1Hz，1H)，7.39(d，J＝1.7Hz，1H)，7.32(d，J＝1.7Hz，1H)，4.72-4.54(m，1H)，4.37-4.22(m，1H)，4.01-3.90(m，2H)，3.84(d，J＝13.0Hz，0.5H)，3.58-3.44(m，4.5H)，3.44-3.36(m，0.5H)，3.03-2.82(m，2.5H)，2.80-2.68(m，1H)，2.32(s，3H)，2.28-1.95(m，2H)，1.93-1.50(m，4H)，1.42-1.17(m，3H)。MS(ESI)：C26H30ClN5O3Theoretical value 495; measured value 496[ M + H]+。
Examples 78 to 87
Examples 78-87 were prepared using a similar procedure as described in example 77.
E78: (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -2-cyanoisonicotinamide
E79: (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide, trifluoroacetate salt
E80: (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-methylbenzamide, trifluoroacetate salt
E81: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6- (fluoromethyl) nicotinamide
E82: n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6- (fluoromethyl) nicotinamide
E83: (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methoxynicotinamide
E84: (S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide
E85: 5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E86: 5-chloro-N- (5-fluoro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide
E87: n- (5-chloro-3- (((S) -3-ethyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) -2-methylphenyl) -6-methylnicotinamide
Figure BDA0001212817760000901
Figure BDA0001212817760000921
Example 88
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide (E88)
Figure BDA0001212817760000922
To a solution of ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((S) -tetrahydrofuran-2-yl) methanone (D74, 100mg), 5-chloro-6-methylnicotinic acid (D5, 48.8mg), HATU (162mg) in DCM (15mL) was added DIPEA (0.099 mL). The mixture was stirred at room temperature overnight. Cold water (30mL) was added and the aqueous layer was extracted with DCM (2X 30 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluting with PE: EA ═ 50% to 100%) and preparative HPLC to give the title compound (26mg) as a white solid.1H NMR(400MHz，MeOD-d4)：8.94(s，1H)，8.36(s，1H)，7.36(d，J＝1.8Hz，1H)，7.31(d，J＝1.8Hz，1H)，4.74-4.59(m，1.5H)，4.37-4.25(m，1H)，3.97-3.88(m，1H)，3.88-3.80(m，1H)，3.80-3.73(m，0.5H)，3.55-3.46(m，2H)，3.45-3.35(m，0.5H)，3.06-2.95(m，0.5H)，2.88-2.80(m，1H)，2.76-2.72(m，1H)，2.70(s，3H)，2.31(s，3H)，2.27-1.68(m，6H)，1.41-1.22(m，3H)。MS(ESI)：C25H30Cl2N4O3A theoretical value 504; measured value 505[ M + H]+。
Example 89
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide (E89)
To a mixture of ((S) -4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) ((R) -tetrahydrofuran-2-yl) methanone (D75, 100mg), 5-chloro-6-methylnicotinic acid (D5, 48.8mg), and HATU (162mg) in DCM (10mL) was added DIPEA (0.099 mL). The mixture was stirred at room temperature overnight. Cold water (30mL) was added and the aqueous layer was extracted with DCM (2X 30 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluting with EA: PE ═ 0% to 50%) and preparative HPLC to give the title compound (10mg) as a white solid.1HNMR(400MHz，MeOD-d4)：8.94(d，J＝1.6Hz，1H)，8.36(d，J＝1.6Hz，1H)，7.36(s，1H)，7.32(d，J＝4.2Hz，1H)，4.90-4.69(m，1H)，4.64-4.62(m，0.5H)，4.33-4.20(m，1H)，3.97-3.94(m，1H)，3.88-3.81(m，1.5H)，3.53-4.99(m，2H)，3.34-3.33(m，0.5H)，3.04-2.99(m，0.5H)，2.88-2.81(m，1H)，2.75-2.71(m，4H)，2.31(s，3H)，2.26-1.92(m，6H)，1.38-1.25(m，3H)。MS(ESI)：C25H30Cl2N4O3A theoretical value 504; measured value 505[ M + H]+。
Example 90
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide (E90)
Figure BDA0001212817760000932
A mixture of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5, 6-dimethylnicotinamide, dihydrochloride (D89, 100mg), (S) -tetrahydrofuran-2-carboxylic acid (30.0mg), DIPEA (66.8mg), and HATU (147mg) in DCM (2mL) was stirred for 2 hours. The mixture was concentrated and purified by preparative HPLC to give the title compound (10 mg).1H NMR(400MHz，MeOD-d4)：8.82(s，1H)，8.13(s，1H)，7.35(d，J＝2.3Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.73-4.63(m，1.5H)，4.35-4.28(m，1H)，3.96-3.75(m，2.5H)，3.54-3.47(m，2H)，3.43-3.37(m，0.5H)，3.04-2.98(m，0.5H)，2.86-2.83(m，1H)，2.74-2.71(m，1H)，2.59(s，3H)，2.42(s，3H)，2.31(s，3H)，2.26-1.89(m，6H)，1.38-1.25(m，3H)。MS(ESI)：C26H33ClN4O3Theoretical value 484; measured value 485[ M + H]+。
Example 91&92
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide and N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (E91& E92)
To a solution of (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide (D57, 238mg) in DMF (3mL) was added tetrahydrofuran-3-carboxylic acid ((r)83mg), HATU (273mg) and TEA (182mg), and the resulting mixture was stirred at room temperature overnight. The mixture was partitioned between EA and water, the organic layer was washed with brine, dried over anhydrous Na2SO4And (5) drying. After concentration, the mixture was purified by preparative HPLC and further by chiral HPLC to give the title compound (56mg and 54mg) as a yellow solid. Isomer 1:1H NMR(400MHz，DMSO-d6)：10.27(s，1H)，9.21(d，J＝1.8Hz，1H)，8.73(d，J＝1.8Hz，1H)，7.41(d，J＝1.8Hz，1H)，7.29(s，1H)，4.56(brs，0.5H)，4.22-4.19(m，1H)，3.96-3.59(m，5H)，3.50-3.44(m，2H)，3.30-3.26(m，0.5H)，3.22-3.16(m，0.5H)，2.84-2.73(m，4.5H)，2.66-2.63(m，1H)，2.23(s，3H)，2.16-1.86(m，4H)，1.26-1.11(m，3H)。MS(ESI)：C26H30ClN5O3theoretical value 495; measured value 496[ M + H]+. Isomer 2:1H NMR(400MHz，DMSO-d6)：10.28(s，1H)，9.21(d，J＝1.6Hz，1H)，8.73(d，J＝1.6Hz，1H)，7.41(d，J＝1.8Hz，1H)，7.29(s，1H)，4.55(brs，0.5H)，4.25-4.19(m，1H)，3.96-3.64(m，5H)，3.50-3.43(m，2H)，3.29-3.25(m，0.5H)，3.24-3.18(m，0.5H)，2.84-2.74(m，4.5H)，2.66-2.63(m，1H)，2.23(s，3H)，2.18-1.85(m，4H)，1.25-1.12(m，3H)。MS(ESI)：C26H30ClN5O3theoretical value 495; measured value 496[ M + H]+。
Example 93&94
N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide and N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-methoxy-6-methylnicotinamide (E93& E94)
Figure BDA0001212817760000951
To a mixture of tetrahydrofuran-3-carboxylic acid (17.29mg) in DCM (20mL) was added (S) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-Methoxy-6-methylnicotinamide, dihydrochloride (D90, 60mg), HATU (67.9mg), TEA (45.2mg) and the reaction stirred at room temperature overnight. The mixture was partitioned between EA and water, the organic layer was washed with brine, dried over anhydrous Na2SO4And (5) drying. After concentration, the mixture was purified by preparative HPLC followed by further purification by chiral HPLC to give the title compound (5mg and 17mg) as a yellow solid. Isomer 1:1HNMR(400MHz，CDCl3)8.51(s，1H)，7.87(s，1H)，7.79(s，1H)，7.66(s，1H)，7.14(s，1H)，4.77(brs，0.5H)，4.42-4.39(m，0.5H)，4.05-3.81(m，7H)，3.65-3.62(m，0.5H)，3.51-3.32(m，2.5H)，3.20(brs，1H)，2.99-2.93(m，0.5H)，2.83-2.78(m，1H)，2.70-2.67(m，1H)，2.54(s，3H)，2.31-2.14(m，4.5H)，2.05-2.03(m，2H)，1.35-1.23(m，4H)。MS(ESI)：C26H33ClN4O4a theoretical value of 500; measured value 501[ M + H]+. Isomer 2:1H NMR(400MHz，CDCl3)8.52(d，J＝1.8Hz，1H)，7.86(s，1H)，7.82(s，1H)，7.67(d，J＝2.0Hz，1H)，7.15(brs，1H)，4.76(brs，0.5H)，4.43-4.40(m，0.5H)，4.12-3.84(m，7H)，3.62-3.58(m，0.5H)，3.51-3.35(m，2.5H)，3.24-3.15(m，1H)，2.98-2.94(m，0.5H)，2.83-2.79(m，1H)，2.70-2.67(m，1H)，2.54(s，3H)，2.31(s，3H)，2.24-1.98(m，3.5H)，1.37-1.23(m，4H)。MS(ESI)：C26H33ClN4O4a theoretical value of 500; measured value 501[ M + H]+。
Example 95
N- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E95)
Figure BDA0001212817760000961
A mixture of (R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, dihydrochloride (D91, 100mg), (R) -tetrahydrofuran-2-carboxylic acid (25.04mg), HATU (123mg), and DIPEA (0.188mL) in DMF (5mL)Stir at room temperature for 2 hours. The mixture was diluted with water (50mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine and Na2SO4And (5) drying. After concentration, the residue was purified by preparative HPLC to give the title compound (60 mg).1H NMR(400MHz，MeOD-d4)：8.87(s，1H)，8.06(dd，J＝9.8，1.8Hz，1H)，7.36(d，J＝2.3Hz，1H)，7.30(d，J＝2.3Hz，1H)，4.71-4.65(m，1.5H)，4.32-4.28(m，1H)，3.95-3.75(m，2.5H)，3.54-3.47(m，2H)，3.42-3.36(m，0.5H)，3.03-2.98(m，0.5H)，2.85-2.83(m，1H)，2.73-2.71(m，1H)，2.60(d，J＝3.0Hz，3H)，2.30-1.89(m，9H)，1.37-1.24(m，3H)。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 96
N- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E96)
Figure BDA0001212817760000971
A mixture of (R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, dihydrochloride (D91, 100mg), (S) -tetrahydrofuran-2-carboxylic acid (25.04mg), HATU (123mg), and DIPEA (0.188mL) in DMF (5mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (50mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine and Na2SO4And (5) drying. After concentration, the residue was purified by preparative HPLC to give the title compound (60 mg).1H NMR(400MHz，MeOD-d4)：8.87(s，1H)，8.06(dd，J＝9.6，1.2Hz，1H)，7.36(brs，1H)，7.30(brs，1H)，4.72-4.62(m，1.5H)，4.29-4.26(m，0.5H)，4.18(brs，0.5H)，3.98-3.91(m，1H)，3.87-3.80(m，1.5H)，3.54-3.46(m，2H)，3.37-3.33(m，0.5H)，3.04-2.98(m，0.5H)，2.87-2.81(m，1H)，2.74-2.72(m，1H)，2.60(d，J＝3.2Hz，3H)，2.30-1.91(m，9H)，1.38-1.23(m，3H)。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 97
N- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E97)
Figure BDA0001212817760000972
To a solution of (R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, 2 trifluoroacetate (D92, 415mg) in DMF (4mL) was added a solution of (S) -tetrahydrofuran-3-carboxylic acid (137.4mg, 97% ee) in DMF (1mL), followed by HATU (741.3mg) and DIPEA (0.55 mL). The reaction mixture was stirred overnight. The mixture was purified by preparative HPLC and further purified with chiral SFC to give the title compound (20 mg).1H NMR(400MHz，MeOD-d4)：8.87(s，1H)，8.07(dd，J＝9.8，1.7Hz，1H)，7.36(d，J＝2.2Hz，1H)，7.31(d，J＝2.0Hz，1H)，4.67(brs，0.5H)，4.32(d，J＝13.7Hz，0.5H)，4.24(brs，0.5H)，4.06-3.75(m，4.5H)，3.57-3.46(m，2H)，3.46-3.34(m，1.5H)，3.05-2.95(m，0.5H)，2.86(d，J＝11.2Hz，1H)，2.79-2.70(m，1H)，2.60(d，J＝2.9Hz，3H)，2.31(s，3H)，2.26-1.97(m，4H)，1.40-1.19(m，3H)。19F NMR(376MHz，MeOD-d4)-126.9。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 98
N- (5-chloro-2-methyl-3- (((R) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide (E98)
To a solution of (R) -N- (5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide, 2 trifluoroacetate (D92, 415mg) inTo a solution in DMF (4mL) was added a solution of (R) -tetrahydrofuran-3-carboxylic acid (136.7mg, 90% ee) in DMF (1mL) followed by HATU (741.3mg) and DIPEA (0.55 mL). The reaction mixture was stirred overnight. The mixture was purified by preparative HPLC and further purified by chiral SFC to give the title compound (65 mg).1H NMR(400MHz，MeOD-d4)8.87(s，1H)，8.07(dd，J＝9.9，1.6Hz，1H)，7.36(d，J＝2.2Hz，1H)，7.31(d，J＝1.7Hz，1H)，4.66(brs，0.5H)，4.37-4.24(m，1H)，3.99-3.72(m，4.5H)，3.58-3.46(m，2H)，3.45-3.35(m，1.5H)，3.05-2.95(m，0.5H)，2.86(d，J＝11.5Hz，1H)，2.79-2.70(m，1H)，2.60(d，J＝2.9Hz，3H)，2.31(s，3H)，2.28-1.96(m，4H)，1.38-1.20(m，3H)。19F NMR(376MHz，MeOD-d4)-125.4。MS(ESI)：C25H30ClFN4O3A theoretical value 488; found 489[ M + H ]]+。
Example 99
5- ((5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide (E99)
Figure BDA0001212817760000991
To a solution of (S) -5- ((5-chloro-2-methyl-3- ((3-methylpiperazin-1-yl) methyl) phenyl) carbamoyl) -3-fluoro-2-methylpyridine 1-oxide, dihydrochloride (D96, 280mg) in DMF (10mL) was added HATU (333mg), DIPEA (0.612mL) and (R) -tetrahydrofuran-3-carboxylic acid (102mg) at 25 ℃, and the reaction mixture was stirred overnight at 25 ℃. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/2) to give the title compound (140mg) as a white solid. Ms (esi): c25H30ClFN4O4A theoretical value 505; measured value 505[ M + H]+。
Biological data
As noted above, the compounds of formula I are ROR γ modulators and are useful in the treatment of diseases mediated by ROR γ. The biological activity of a compound of formula I can be determined using any suitable assay and tissue and in vivo models for determining the activity of candidate compounds as ROR γ modulators.
Fluorescence energy transfer (FRET) assay
The assay was performed on 384-well plates (Greiner 784076, Longwood, FL) in 50mM NaF, 50mM 3- (N-morpholino) propanesulfonic acid, pH 7.5, 50. mu.M 3- [ (3-cholamidopropyl) dimethylamino]-propanesulfonate, 0.1mg/mL bovine serum albumin and 10mM dithiothreitol. The total volume was 10. mu.L/well. The europium-labeled SRC1 solution was prepared by adding the appropriate amounts of biotinylated SRC and europium-labeled streptavidin (PerkinElmer Life and analytical sciences, Waltham, Mass.) to the test buffer at final concentrations of 27 and 3.3nM, respectively. Allophycocyanin (APC) -labeled-LBD solutions were prepared by adding appropriate amounts of biotinylated ROR γ -LBD and APC-labeled streptavidin (CR)130-100 parts of; PerkinElmer Life and Analytical Sciences) to a final concentration of 33nM each. After incubation for 15min at room temperature, a 20-fold excess of biotin was added to block the remaining free streptavidin. Equal volumes of europium-labeled SRC-and APC-labeled ROR γ -LBD were then mixed with 0.2 μ M of the surrogate agonist N- (2-chloro-6-fluorobenzyl) -N- ((2 '-methoxy- [1, 1' -biphenyl)]-4-yl) methyl) benzenesulfonamide (Zhang, w., et al, mol. pharmacol.2012, 82, 583-. The 384-well test plate had 100nL of test compound in DMSO pre-dispensed into each well. Plates were incubated at room temperature for 1h and then read on a viewlux (perkinelmer Life and analytical sciences) in LANCE mode configured for europium-APC labeling. Data were collected and then analyzed by Activitybase.
Dual Fluorescence Resonance Energy Transfer (FRET) assay
This test is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand-dependent manner. ROR γ is a typical nuclear receptor, i.e., it has an AF2 domain in the Ligand Binding Domain (LBD) that interacts with a co-activator. The site of interaction is mapped to the LXXLL motif of the coactivator SRC1(2) sequence. The short peptide sequence containing the LXXLL motif mimics the behavior of the full-length co-activator.
This assay measures ligand-mediated interaction of the coactivator peptide with the purified bacterially expressed ROR γ ligand binding domain (ROR γ -LBD) to indirectly assess ligand binding. In the absence of ligand, ROR γ has a basal level of interaction with the co-activator SRC1(2), making it possible to find ligands that inhibit or enhance ROR γ/SRC1(2) interactions.
Material
Generation of ROR gamma-LBD bacterial expression plasmid
The human ROR γ ligand binding domain (ROR γ -LBD) is expressed as an amino-terminal poly-histidine-tagged fusion protein in e.coli strain BL21(DE 3). The DNA encoding the recombinant protein was subcloned into a modified pET21a expression vector (Novagen). The modified polyhistidine tag (MKKHHHHHHLVPRGS) was fused in frame (frame) to residue 263-518 of the human ROR γ sequence.
Protein purification
Approximately 50g of E.coli cell pellet was resuspended in 300mL lysis buffer (30mM imidazole pH 7.0 and 150mM NaCl). Cells were lysed by sonication, and cell debris was removed by centrifugation at 20,000g for 30 minutes at 4 ℃. The clear supernatant was filtered through a 0.45uM cellulose acetate membrane filter. The clear lysate was loaded onto a column (XK-26) packed with Probond Nickel chelate resin (Invitrogen) pre-equilibrated with 30mM imidazole pH 7.0 and 150mM NaCl. After washing with equilibration buffer to baseline uptake, the column was developed with a gradient of 30-500mM imidazole pH 7.0. The column fractions containing ROR γ -LBD protein were pooled and concentrated to a volume of 5 ml. The concentrated protein was loaded onto a Superdex 200 column, which was pre-equilibrated with 20mM Tris-Cl pH 7.2 and 200mM NaCl. Fractions containing the desired ROR γ -LBD protein were pooled together.
Protein biotinylation
Purified ROR γ -LBD was buffer exchanged as follows: dialysis was performed thoroughly [3 changes of at least 20 volumes (>8000X) ] against PBS [100mM sodium phosphate, pH 8 and 150mM NaCl ]. The concentration of ROR γ -LBD in PBS was about 30 uM. NHS-LC-Biotin (Pierce) was added in a 5-fold molar excess to the minimal volume of PBS. The solution was incubated at ambient room temperature for 60 minutes and not mixed gently. Modified ROR gamma-LBD relative to 2 buffer change-containing 5mMDTT, 2mMEDTA and 2% sucrose TBS pH 8.0-dialysis, each time at least 20 times volume. The modified protein was dispensed into aliquots, frozen on dry ice, and stored at-80 ℃. Mass spectrometry analysis of biotinylated ROR γ -LBD was performed to reveal the extent of modification by the biotinylation reagent. Generally, about 95% of the proteins have at least one biotinylation site, and the overall degree of biotinylation follows a normal distribution of multiple sites ranging from 1-5. Similar methods were used to generate biotinylated peptides corresponding to amino acids 676 to 700(CPSSHSSLTERHKILHRLLQEGSPS) of the co-activator of the steroid hormone receptor SRC1 (2).
Testing
Preparation of europium-labeled SRC1(2) peptide: a solution of biotinylated SRC1(2) was prepared as follows: from a 100uM stock solution, the appropriate amount of biotinylated SRC1(2) was added to a buffer containing 10mM freshly added DTT (from solids) to give a final concentration of 40 nM. An appropriate amount of europium-labeled streptavidin was then added to the biotinylated SRC1(2) solution in the tube to give a final concentration of 10 nM. The tube was gently inverted and incubated at room temperature for 15 minutes. A 20-fold excess of biotin from a 10mM stock solution was added, and the tubes were then gently inverted and incubated at room temperature for 10 minutes.
Preparation of APC-labeled ROR γ -LBD: biotinylated ROR γ -LBD solution was prepared as follows: the appropriate amount of biotinylated ROR γ -LBD was added from the stock solution to a buffer containing 10mM freshly added DTT (from solid) to give a final concentration of 40 nM. An appropriate amount of APC-labeled streptavidin was then added to the biotinylated ROR γ -LBD solution in the tube to give a final concentration of 20 nM. The tube was gently inverted and incubated at room temperature for 15 minutes. A 20-fold excess of biotin from a 10mM stock solution was added, and the tubes were then gently inverted and incubated at room temperature for 10 minutes.
Equal volumes of the europium-labeled SRC1(2) peptide and APC-labeled ROR γ -LBD described above were gently mixed together to give 20nM ROR γ -LBD, 10nM APC-streptavidin, 20nM SRC1(2), and 5nM europium-streptavidin. The reaction mixture was incubated for 5 minutes. Using a Thermo Combi multistrop 384stacker device, 25ul of reaction mixture/well was added to a 384 well test plate containing 1ul of test compound per well in 100% DMSO. Plates were incubated for 1 hour and then read in Lance mode for EU/APC on ViewLux.
Jurkat cell luciferase assay
ROR γ is known to bind to CNS (conserved non-coding sequence) enhancer elements in the IL17 promoter. In this test, ROR γ activity was evaluated indirectly using a luciferase reporter construct containing the human IL17 promoter with ROR γ -specific CNS enhancer elements. Inhibition of ROR γ activity by the compound will result in a decrease in luciferase activity in Jurkat cells transfected with the reporter construct.
Material
Jurkat cell line
For the luciferase reporter plasmid, the 3Kb human IL17 promoter containing the ROR γ -specific CNS enhancer element was PCR amplified from human genomic DNA and then cloned into the pGL4-Luc2/hygro reporter plasmid sequenced as the XhoI-HindIII (1.1Kb) and KpnI-XhoI (1.9Kb) fragments. For the 1.1Kb fragment, the human IL17 proximal promoter region was amplified from genomic DNA of 293T cells using PCR using the following primers: forward primer, 5-CTCGAGTAGAGCAGGACAGGGAGGAA-3' (the XhoI site is underlined) and the reverse primer, 5-AAGCTTGGATGGATGAGTTTGTGCCT-3' (HindIII site underlined). The 1.1kb DNA band was cleaved, purified, and inserted into pMD19-T Simple vector (Takara). After confirmation of DNA sequencing, the 1.1kb DNA was digested with XhoI and HindIII and inserted into pGL4.31[ luc2P/GAL4UAS/Hygro]The XhoI/HindIII site of (Promega) yielded the pIL17-1kb-luc reporter construct. For the 1.9Kb fragment, the human IL17 promoter region was amplified from genomic DNA using PCR using the following primers: forward primer, 5-GGTACCTGCCCTGCTCTATCCTGAGT-3' (KpnI site underlined) and reverse primer, 5-CTCGAGTGGTGAGTGCTGAGAGATGG-3' (the XhoI site is underlined). The resulting 1.9kb DNA band was cut, gel purified, and cloned into pMD19-T Simple vector (Takara). DNA sequencing analysis revealed that there were three point mutations, but none affected ROR γ binding. The luciferase reporter plasmid "pIL 17-3 kb-CNS-luc." was generated by releasing the 1.9kb DNA fragment by double digestion with KpnI and XhoI and inserting it into pIL17-1 kb-luc. To express ROR γ t, the full-length cDNA of human ROR γ t identical to the disclosed sequence NM — 001001523 was cloned into pcdna3.1 at the KpnI-NotI cloning site, resulting in ROR γ t over-expression plasmid "cDNA 3.1dhror γ 49-8".
Luciferase reporter plasmids and ROR γ t overexpression plasmids were transfected into Jurkat cell lines and stable clones were then identified. The stable clones were cultured in 10% dialyzed FBS in RPMI (1640) containing 800ug/ml geneticin and 400ug/ml hygromycin.
Testing
Compounds were dissolved in DMSO at three concentrations (10mM, 400uM, and 16uM) and then dispensed into 384-well test plates at 40nl, 12.5nl, and 5nl, respectively. The volume was adjusted with pure DMSO to give a final uniform volume of 40 nl. The Jurkat cells were counted and centrifuged. The growth medium was discarded and the cells were then resuspended at 1E-6/ml with test medium (RPMI without phenol red). Cells are added to each compound in the test plate. The cells were either untreated or treated with CD3 microbeads (miltenyi biotec) at 1ul beads per 500,000 cells. Cells were cultured overnight and tested for luciferase (Promega). Data were collected via ViewLux (using the luciferase Greiner 384 setup).
Th17 cell differentiation assay
ELISA
Mouse CD4+ cells were purified using the CD4+ T cell isolation II kit according to manufacturer's (Miltenyi Biotec) instructions, 96-well plates were pre-coated with anti-mCD 3 antibody, uncoated wells served as controls, CD4+ cells were resuspended in RPMI 1640 complete medium and then added to the 96-well plates, then Cytokine mixtures (Cytokine cocktails) and compounds were added to the wells the antibodies and cytokines used in the tests (all from the R & D system) were selected from the group consisting of anti-mCD 3, anti-mCD 28, anti-mIFN γ, anti-mIL 4, mIL-6, mIL-23, mIL-1 β, hTGF- β 1, medium was incubated at 37 ℃ for 3 days, then supernatants were collected for ELISA, IL-17ELISAs was performed according to manufacturer's (R & D system) instructions, results were analyzed using Prism software, and non-linear regression was used to determine 50C.
Intracellular staining
The Th17 differentiation medium described above was maintained for 5 days and cells were then analyzed by IL-17 and IFN- γ intracellular staining according to the manufacturer's instructions (BD Biosciences).
Test data
If multiple assays are performed, the data below represent the average pIC of the results of the multiple tests50The value is obtained. It is understood that the data presented below may vary reasonably depending on the particular conditions and procedures used by the person performing the test.
All exemplary compounds were assayed in the FRET assay described above, except examples 97-99. All test compounds were found to have pIC's of 5-850. For example, the compounds of examples 57 and 91 were found to have pIC of about 6.9 and 6.6, respectively50The value is obtained.
All exemplary compounds were assayed in the dual FRET assay described above, except for examples 14, 18, 45, 46, 53, 66, 74, 75, 81, 82, 93, 97, and 98. All test compounds were found to have pIC's of 5-850. For example, the compounds of examples 57 and 91 were found to have pIC's of approximately 6.7 and 6.1, respectively50The value is obtained.
All of the exemplified compounds were assayed in the Jurkat cell luciferase assay described above, except for examples 2-6, 10, 15, 16, 20, 21, 28, 29, 34, 35, 38, 39, 44-55, 63, 64, 68-72, 75-79, 81-84, 87, 89, and 95-99. All test compounds were found to have pIC's of 5-950. For example, the compounds of examples 57 and 91 were found to have pIC's of approximately 7.6 and 7.9, respectively50The value is obtained.
All exemplary compounds were tested for Th17 cell differentiation as described aboveExcept for examples 20, 21, 38, 39, 48-51, 54, 55, 61-64, 66, 67, 77, 79, 81, 82 and 95-99. All test compounds were found to have pIC's of 6-950. For example, the compounds of examples 57 and 91 were found to have pIC of approximately 7.09 and 7.76, respectively50The value is obtained.
EAE study
Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis. The ability of test compounds to improve EAE was measured in the EAE study. Wild-type mice of strain C57BL/6(B6) were maintained under pathogen-free conditions. EAE is induced as follows: 100ng pertussis toxin (List Biological Laboratories) was injected intravenously and then treated with MOG in PBS on day 035-55Subcutaneous immunisation was carried out with an emulsion of peptide (300. mu.g/mouse) and an equal volume of complete Freund's adjuvant (Difco Laboratories) containing 5mg/ml of heat-inactivated Mycobacterium tuberculosis H37Ra, followed by another intravenous injection of 100ng of pertussis toxin on day 2 as described previously (Wang et al (2006) J.Clin.invest.116: 2434-2441). For treatment of EAE, each compound or vehicle PBS was administered orally, twice a day, starting on day 0at different doses selected from 3, 10, 30 and 100 mg/kg. Mice were scored for daily disease severity using the EAE scoring system (Wang et al (2006) j. clin. invest.116: 2434-2441): 0, no obvious signs of disease; 1, weak tail (limb) or weakness of hind limb but not both; 2, flaccid tail and paraparesis (weakness, incomplete paralysis of one or both hind limbs); paraplegia (complete paralysis of both hind limbs); 4, paraplegia with forelimb weakness or paralysis; 5, moribund state or death. Clinical score data can be expressed as mean ± s.e.m.
In vitro transdermal Studies
In vitro transdermal studies are aimed at predicting the level of transdermal penetration obtained by compounds of topical formulations against psoriasis. This test, together with the intrinsic potency of the compound, is used to predict the likelihood of success of the compound in conjugation with the target. The higher the ratio of transdermal penetration to intrinsic efficacy, the higher the ratio of local skin concentration to intrinsic efficacy and, therefore, the greater the likelihood of compound engagement with the target in a topical formulation.
The compounds were prepared in an aqueous cream modified at pH 6.
Aqueous cream composition
Figure BDA0001212817760001051
The study can be performed with dermomed human abdominal skin from three skin donors using 2cm2Franz diffusion cells. The receiving fluid consisted of bovine serum albumin (4% w/v) in 0.1% w/v sodium azide/phosphate buffered saline and could then be heated at 37 ℃ in order to reach 32 ℃ at the skin surface. The cream formulation may be applied to the donor side at a dose of 10mg, i.e., 5mg/cm2. The samples can be taken at the following time points: t is 0, 3, 6, 9 and 24 h. The recipient sample may then be tested as follows: a method based on precipitation of proteins with acetonitrile was used, followed by LC/MS analysis. Can be used for 24 hr per cm2The API (in various compositions) of the individual permeating to the recipient compartment determines the transdermal flux (expressed as ng/cm)2In hours).
Imiquimod-induced skin inflammation
Imiquimod is an immunomodulator that effectively activates specific Toll-like receptors (e.g., TLR7) and induces stimulation/inflammation of skin requiring the immune system IL23R/ROR γ/IL17 axis (van der Fits et al, (2009) JImmunol; 182: 5836-5845; Gray et al, (2013) Nature Immunol; Jun; 14(6): 584-92.) the imiquimod-induced skin inflammation model can be used to assess the ability of ROR γ inhibitors to reduce Th 17-driven inflammation in mice, for ear thickness measurement using a sizer (Mitutto PK-0505) measuring ear only skin inflammation model, 8-12 week old female C57/6 NTac mice can be obtained from Taconic (Hudson, NY) and given a daily local dose of 10mg quinate (Mituttoo PK-0040505) and purified via a recombinant DNA-gel cream (Msancow) or Biogene expression profile probe (Mgeleak 2-27, 20) as anti-mouse protein (Mgeleak protein) and/protein (Mgeleave) by oral administration in a bolus) as a bolus, protein, and/protein (Mgeleak 2) in a bolus injection, protein, and/protein (Mgele) in mice, protein, such a kit) as a vaccine, protein.
Human peripheral blood CD4+ T cell culture and cytokine analysis
Human samples were cryopreserved human CD4+ T cells purchased from AllCells, LLC and/or Stemcell Technologies, Inc. the CD4+ T cells were differentiated into the Th17 subtype by culturing 5 days in Iscoecco Modified Dulbecco Medium (IMDM) coated with anti-CD 3 antibody (2 μ g/mL) in tissue culture plates containing anti-CD 3 antibody (2 μ g/mL) containing 10% HI-FBS, 55 μ M2-mercaptoethanol and anti-CD 28 (8293 g/mL) containing low density interfering compounds in triplicate culture wells containing no disturbing factors (msdsyk 5. g/mL) to detect directly after incubation of cells in triplicate cells containing no interfering factors (msdsid) at 25 ℃ and no interfering factors (msdsyk) in triplicate culture plates containing no interfering factors after incubation of cells with western blot) in a 5 days of a tpo &5 Th17 shift cocktail (containing IL-1 β (10ng/mL), IL-6(30ng/mL), TGF 2 (0.5ng/mL), IL-21(10ng/mL), IL-4(10 μ g/mL).
Application method
The compounds of formula I are ROR γ modulators and are useful in the treatment of diseases mediated by ROR γ, in particular autoimmune or inflammatory diseases. Examples of inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, crohn's disease, inflammatory bowel disease, sjogren's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type i diabetes, neuromyelitis optica, myasthenia gravis, uveitis, guillain-barre syndrome, psoriatic arthritis, graves ' disease, and allergies. Thus, in another aspect, the invention relates to methods of treating autoimmune and inflammatory diseases mediated by rory.
In another aspect, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
In another aspect, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and autoimmune diseases mediated by rory.
In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.
In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of ankylosing spondylitis.
In another aspect, the present invention relates to a method of treating an inflammatory or autoimmune disease mediated by rory, comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In still other aspects, the invention relates to a method of treating multiple sclerosis comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In still other aspects, the invention relates to a method of treating ankylosing spondylitis, comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease mediated by rory.
In still other aspects, the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of multiple sclerosis.
In still other aspects, the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ankylosing spondylitis.
As used herein, "treating" or "treatment" in relation to a condition means: (1) ameliorating or preventing one or more biological manifestations of the disorder, (2) interfering with (a) one or more points in a biological cascade responsible for or responsible for the disorder or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
As noted above, "treatment" of a disorder includes prophylaxis of the disorder. Those skilled in the art will appreciate that "prevention" is not an absolute term. Medically, "preventing" is understood to mean prophylactic administration of a drug to substantially reduce the likelihood or severity of, or delay the onset of, a condition or its biological manifestations.
The compounds of the invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, rectal and inhalation administration. Parenteral administration means administration routes other than enteral, transdermal or inhalation, usually injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Inhalation means administration to the lungs of a patient, whether by inhalation through the mouth or nasal passages. Topical administration includes administration to the skin as well as intraocular, otic, intravaginal and intranasal administration.
The compounds of the present invention may be administered once for a given period of time or in multiple doses at different time intervals according to a dosing schedule. For example, the dose may be administered one, two, three or four times daily. The dosage may be administered until the desired therapeutic effect is achieved, or may be administered indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by one skilled in the art. In addition, the appropriate dosage regimen (including the duration of the dosage regimen) of the compound of the invention will depend upon the condition to be treated, the severity of the condition to be treated, the age and physical condition of the individual to be treated, the medical history of the individual to be treated, the nature of concurrent therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of those skilled in the art. The skilled artisan will also appreciate that suitable dosing regimens may be adjusted according to the individual's response to the dosing regimen or as the individual needs change over time.
Typical daily dosages may vary depending upon the particular route of administration selected. Typical daily doses for oral administration are in the range of 0.1mg to 1000 mg. Typical daily dosages for topical administration are from about 0.001% to about 10% w/w (weight percent), and preferably from about 0.01% to about 1% w/w.
In addition, the compounds of the present invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the present invention is a functional derivative of the compound that, upon administration to a subject, ultimately releases the compound of the present invention in vivo. Administration of the compounds of the present invention as prodrugs may enable one skilled in the art to perform one or more of the following: (a) modulation of the onset of action of the compound in vivo; (b) modulating the duration of action of the compound in vivo; (c) modulating transport or distribution of the compound in vivo; (d) modulating the solubility of the compound in vivo; and (e) overcoming the side effects or other difficulties suffered by the compounds. Typical functional derivatives useful in the preparation of prodrugs include modifications of the compounds which are cleaved in vivo either chemically or enzymatically. Such modifications, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.
Composition comprising a metal oxide and a metal oxide
The compounds of the present invention are typically (but not necessarily) formulated into pharmaceutical compositions prior to administration to a subject. Thus, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form, wherein a safe and effective amount of a compound of the present invention may be extracted and then administered to an individual, for example, in the form of a powder or slurry. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention will generally contain from 0.1mg to 1000 mg.
The pharmaceutical compositions of the invention will generally contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments, a pharmaceutical composition of the invention contains two compounds of the invention. In addition, the pharmaceutical compositions of the present invention may optionally further comprise one or more additional pharmaceutically acceptable compounds.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition or vehicle involved in a form of administration or compatible with a pharmaceutical composition. When mixed, each excipient must be compatible with the other ingredients of the pharmaceutical composition so that interactions that would substantially reduce the efficacy of the compounds of the invention when administered to an individual and interactions that would cause the pharmaceutical composition to be pharmaceutically unacceptable are avoided. Furthermore, the purity of each excipient must, of course, be sufficiently high to render it pharmaceutically acceptable.
The compounds of the invention and one or more pharmaceutically acceptable excipients are generally formulated in a dosage form suitable for administration to a subject by a desired route of administration. For example, dosage forms include those (1) suitable for oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) dosage forms suitable for parenteral administration, such as sterile solutions, suspensions and powders for reconstitution; (3) dosage forms suitable for transdermal administration, such as transdermal patches; (4) dosage forms suitable for rectal administration, e.g., suppositories; (5) formulations suitable for inhalation, such as dry powders, aerosols, suspensions and solutions; and (6) dosage forms suitable for topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected according to the particular function being performed in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the preparation of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the preparation of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the transport or carriage of a compound of the invention from one organ or part of the body to another organ or part of the body following administration to a subject. Certain pharmaceutically acceptable excipients may be selected for their ability to improve patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. One skilled in the art will appreciate that certain pharmaceutically acceptable excipients may be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Those having skill and knowledge in the art will be able to select suitable pharmaceutically acceptable excipients for use in the present invention in appropriate amounts. Furthermore, there are many resources available to those skilled in the art which describe pharmaceutically acceptable excipients and which are usefulSelecting suitable pharmaceutically acceptable excipients. Examples includeRemington's Pharmaceutical Sciences(Mack Publishing Company)，The Handbook of Pharmaceutical Additives(Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and thePharmaceutical Press)。
the pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described inRemington's Pharmaceutical Sciences(Mack publishing company).
In one aspect, the invention relates to solid oral dosage forms, such as tablets or capsules, comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, glucose, mannitol, sorbitol, starches (e.g., corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starches (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose). The oral solid dosage form may also comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

Claims (20)

1. A compound of formula I:
Figure FDA0002123815050000011
wherein:
R1comprises the following steps:
-5-6 membered monocyclic heteroaryl, which is optionally substitutedIs substituted by: i) optionally with CF3Or C substituted by CN1-C5An alkyl group; ii) CH2F; or iii)1-2 substituents independently selected from: halogen, methyl, methoxy and CN; wherein the 5-6 membered monocyclic heteroaryl is selected from: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and tetrazolyl; or
-phenyl substituted with 1-2 substituents independently selected from: CN, halogen and methyl;
R2is C1-C3An alkyl group;
R3is halogen;
R4is H;
R5is C1-C3An alkyl group;
R6is H or methyl; and
R7is tetrahydrofuranyl or tetrahydropyranyl, wherein the tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with methyl.
2. A compound or salt of claim 1, wherein R1Is phenyl substituted by CN.
3. A compound or salt of claim 1, wherein R1Is phenyl substituted by CN and F.
4. A compound or salt of claim 1, wherein R1Is pyridyl substituted with: i) methyl and F; ii) methyl and Cl; iii) methyl and CN; or iv) CN and F.
5. A compound or salt of claim 1, wherein R1Is pyridyl substituted with: i) methyl and F.
6. The compound or salt of any one of claims 1-5, wherein R2Is a firstAnd (4) a base.
7. The compound or salt of any one of claims 1-5, wherein R3Is Cl.
8. The compound or salt of any one of claims 1-5, wherein R5Is methyl.
9. The compound or salt of any one of claims 1-5, wherein R6Is H.
10. The compound or salt of any one of claims 1-5, wherein R7Is tetrahydrofuranyl.
11. The compound or salt of any one of claims 1-5, wherein R7Is tetrahydropyranyl.
12. A compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(S) -N- (5-chloro-2-methyl-3- ((3-methyl-4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-5-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyanobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -3-cyano-4-fluorobenzamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -5-cyano-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
n- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide;
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide; and
5-chloro-N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((R) -tetrahydrofuran-2-carbonyl) piperazin-1-yl) methyl) phenyl) -6-methylnicotinamide.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is N- (5-chloro-2-methyl-3- (((S) -3-methyl-4- ((S) -tetrahydrofuran-3-carbonyl) piperazin-1-yl) methyl) phenyl) -5-fluoro-6-methylnicotinamide.
14. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
15. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
16. A compound according to any one of claims 1 to 5, 12 or 13, or a pharmaceutically acceptable salt thereof, for use in therapy.
17. A compound according to any one of claims 1 to 5, 12 or 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.
18. A compound according to any one of claims 1 to 5, 12 or 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of ankylosing spondylitis.
19. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of multiple sclerosis.
20. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ankylosing spondylitis.
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